TMT对原代海马神经元损伤与BDNF保护作用研究
摘要
研究背景和目的：
三氯甲基锡(Trimethyltin,TMT)是一种重要的职业危害毒物，也是一种重要的环境污染物。急性TMT暴露可引起多系统主要包括神经系统的损害。TMT作用于中枢神经系统，主要损伤作用机制为引起神经细胞凋亡，引起神经系统炎性反应，对神经组织造成氧化损伤等。TMT可以选择性地诱导大脑边缘系统，特别是海马神经元死亡，造成神经系统损伤效应。研究表明，BDNF在中枢神经系统的主要作用是调节海马神经突触可塑性。TMT暴露的大鼠大脑BDNF表达下调，而过表达BDNF的神经元具有拮抗TMT神经毒性的作用。但TMT对大脑神经元的损伤机制特别是对神经元树突棘的损伤研究还不清楚，并且BDNF拮抗TMT损伤发挥神经保护作用的机制尚待进一步研究。因此，本课题选取TMT及BDNF为研究内容，试图理解TMT对神经元的损伤作用机制及BDNF保护作用的分子机制，并为治疗和预防TMT职业暴露造成的神经元损伤提供思路。
突触可塑性指突触效率的功能性增强或降低，同时神经信号传递强度的变化伴随着神经元突触的结构变化。并且，BDNF参与调节活动依赖的树突棘发育及可塑性。近期研究表明BDNF可以作为成年脑中活动依赖性调节因子参与调控神经结构和功能变化。BDNF从树突分泌出来后，立即与神经营养因子受体TrkB结合，进而促进突触前神经递质的释放并且增加突触后蛋白的转录翻译水平。Tau蛋白主要表达于神经元树突轴，独立或与其他微管相关蛋白协同调节树突轴微管功能。在神经细胞中，tau蛋白与细胞膜相联系或与微管发生相互作用。Tau蛋白表达或者结构的变化可能影响其稳定微管蛋白的功能。在生理条件下，tau蛋白可能在不同的位点发生磷酸化改变，进而影响其稳定微管的功能。成熟神经元可以利用微管的动态性保持细胞体系的弹性，以适应神经网络发生的各种变化。
方法：
第一部分TMT对神经元毒性的观察
以原代培养的胚胎期18天海马神经元为模型，用TMT处理后，用CCK-8的方法观测BDNF对TMT的保护作用，观察TMT处理后神经元树突棘形态的影响以及BDNF的保护作用，并明确TMT对神经元树突棘毒性的特征；
第二部分BDNF对神经元突触和树突棘生长影响的观察
以原代培养的胚胎期18天海马神经元为模型，用BDNF处理，观察对原代培养海马神经元突触生长和树突棘形态的影响；利用质粒转染GFP或RFP标记原代海马神经元树突棘，细胞免疫荧光化学观测tau蛋白和微管的共定位情况，突触综合体测量BDNF处理后突触生长的变化，westernblot检测tau蛋白及其磷酸化变化，明确BDNF处理海马神经元后，神经元的形态突触可塑性的变化以及tau蛋白所起的作用；
第三部分BDNF对Tau蛋白磷酸化及细胞分布的观察
以RA分化的人神经母细胞瘤SH-SY5Y和原代培养的胚胎期18天海马神经元为模型，用BDNF处理后，采用细胞免疫荧光化学的方法观察tau蛋白的亚细胞分布情况，Leica软件测量SH-SY5Y细胞的突触生长情况，westernblot检测tau蛋白表达变化,明确tau蛋白亚细胞分布和BDNF处理后细胞的突触生长的关系；
结果：
第一部分TMT引起树突棘的异常形态改变
TMT处理体外培养14天的原代海马神经元24h，CCK-8检测细胞活力显著下降；加入BDNF与TMT共刺激后，CCK-8检测细胞活力无显著上升。原代海马神经元体外培养7天时转染GFP质粒，培养至20天，TMT和/或BDNF处理24h后固定细胞，共聚焦显微镜发现TMT处理后神经元树突棘出现异常圆形增大。加入BDNF处理后，树突棘的异常圆形增大有减少的趋势。BDNF与LiCl共刺激能够同样使神经元树突棘出现与TMT处理后高度相似的异常圆形增大。Westerbnlot实验结果表明，BDNF处理后可以同时在原代培养的海马神经元磷酸化Akt和ERK。而锂单独似乎不能影响Akt和ERK的磷酸化状态。当锂与BDNF同时作用时，BDNF诱导的ERK的磷酸化没有影响，但锂却抑制BDNF诱导的Akt磷酸化。TMT以及BDNF和LiCl联合作用产生的神经元树突棘异常增大可能与ERK与PI3K-Akt之间的cross-talk平衡被破坏有关。
第二部分BDNF通过tau蛋白调节突触和树突棘生长
BDNF处理体外培养14天的海马神经元24h，Tau蛋白的表达都显著升高，Ser262位点的磷酸化状态在BDNF刺激后具有下降的趋势。细胞免疫荧光化学实验也证明tau蛋白与微管蛋白在BDNF处理后的共定位得以增强。BDNF处理后tau蛋白的表达变化与树突棘密度的增加一致。运用shRNA技术在体外培养7天时下调tau蛋白表达水平后，培养至21天海马神经元树突棘密度显著下降。并且在shRNA下调tau蛋白的海马神经元中，24h BDNF刺激不能增加神经元的树突棘密度。
第三部分BDNF调节tau蛋白的磷酸化与亚细胞分布
通过免疫细胞化学方法，我们发现在未分化的缺乏神经突起的SH-SY5Y细胞中，tau蛋白形成一个球体。相反，在维甲酸诱导分化5天的SH-SY5Y细胞中，tau蛋白分散分布在神经细胞突起和胞体中。通过Western blot检测方法，我们发现维甲酸的处理也增加了总tau蛋白水平而降低tau蛋白Ser262磷酸化水平。Tau蛋白表达上调和tau蛋白ser262磷酸化水平的下调与神经细胞突起长度呈相关性(相关因子分别为r=0.94和r=-0.98)。当原E18海马神经元用微管解聚剂nocodazole处理后，新生的神经元突起丢失并且发生tau蛋白转移到胞体的现象。这种远离突起的过程可以被BDNF一定程度上逆转。
研究结论
基于以上研究结果，我们得出以下研究结论：TMT处理体外培养的海马神经元后发现神经元的树突棘出现异常的增大现象，可能是TMT的神经毒性表现。BDNF具有保护TMT树突棘损伤的潜力。TMT处理以及BDNF和LiCl联合作用产生的神经元树突棘异常增大可能与ERK与Akt之间的cross-talk平衡被破坏有关。BDNF能够调节原代海马神经元tau蛋白的表达,这样的调节具有剂量依赖关系和时效依赖关系。通过质粒转染原代培养海马神经元，下调tau蛋白表达，BDNF刺激神经元树突棘生长的现象被抑制，说明tau蛋白可能参与了BDNF调节神经元突触及树突棘生长的信号通路。进一步实验表明，BDNF调节树突棘可塑性的作用可能是通过调节tau蛋白的表达量进而影响tau蛋白稳定微管能力来实现的；tau蛋白Ser262位点的磷酸化水平，总tau蛋白的表达量以及tau蛋白的亚细胞分布变化与神经细胞突触生长的显著相关，tau蛋白的表达增加以及Ser262位点的去磷酸化可能以利于神经细胞突触的生长。本实验为TMT的神经毒性特别是对海马神经元树突棘的损伤提供新的证据，也揭示了BDNF可以通过tau蛋白调节突触以及树突棘生长发挥神经保护作用。
Background
TMT is an important occupation poison, and is a risk factor of environmental pollution.Acute TMT exposure could cause multi system including nerve system damage. The maindamage caused by TMT in the central nervous systemincludes apoptosis of nerve cells,neuronal inflammation and oxidative damage of the nervous tissue. TMT can selectivelyinduce the limbic system, especially caused the hippocampal neuronal death effect. BDNFplays a main role in regulating hippocampal synaptic plasticity in the central nervoussystem. Rat brain exposed to TMT showed reduced BDNF expression and the neurons overexpression of BDNFcould antagonist the neurotoxicity of TMT. But the mechanism ofTMT damage to the brain neurons especially the damage to neuronal dendritic spines isunclear, and the mechanisms of BDNF antagonist TMT damage effect remains to be furtherstudied.Therefore, this paper chooses BDNF and TMT as the research content, trying tounderstand TMT damage to the neural synaptic plasticity and the molecular mechanism ofBDNF protective effect, in order to provide clues for the treatment and prevention of TMToccupation exposure on synaptic plasticity damage.
Synaptic plasticity refers to the functional synaptic efficiency enhanced or reduced, atthe same time transmission of neural signal intensity changes accompanied by structuralchanges in neuronal synapse. Moreover, brain derived neurotrophic factor involved in thedevelopment and plasticity of dendritic spines of regulating activity dependent. Recentstudies show that BDNF can be used as the adult brain activity dependent regulation offactors involved in the changes of structure and function of regulating nerve. BDNFsecreted from the dendrites, immediately combined with neurotrophic factor receptor TrkB,and then promote the presynaptic neurotransmitter release and increase the level oftranscription and translation of the postsynaptic protein. Tau protein was mainly expressedin the neuronal dendritic shaft, independent or associated with other tubulin co regulation ofdendritic shaft microtubule function. In nerve cells, tau protein and cell membrane associated or interact with microtubules. Expression of Tau protein or structure may affectthe stability of microtubule protein function. Under physiological conditions, tau proteinphosphorylation changes may occur at different sites, thereby affecting its microtubulestabilizing function. Mature neurons can use dynamic microtubules maintain cell system, toadapt to the changes of neural network place.
Methods
Part I: To observe the neurotoxity of TMT
Primary cultures of embryonic day18hippocampal neurons were used as model. Afterthe treatment with TMT, the protective effect of BDNF was observed by CCK-8assay;neuronal dendritic spine morphology were observed after treatment with TMT and TMTplus BDNF.We would like to address the characteristic of TMT toxicity on dendritic spine.
Part II: To observe the effect of BDNF in the regulating synaptic plasticity
Primary cultured embryonic day18(E18) hippocampal neurons of embryonic day18was treated by BDNF, the effect of the hippocampal synaptic growth and dendritic spineswas observed; GFP, RFP plasmids were transfected into primary hippocampal neurons tolabel dendritic spines; colocalization of tau protein and the microtubules was examined byimmunocyochemistry; synaptic complex was measured after treatment with BDNF; tauprotein expression and phosphorylation was detected by Westernblot. These experimentsare set to investigate the role of tau protein in neuronal morphology changes in synapticplasticity of hippocampal neurons.
Part III: To observe the effect of BDNF on Tau phosphorylation and celldistribution
Retinoic acid (RA) differentiated human neuroblastoma SH-SY5Y and primary cultureof embryonic day18hippocampal neurons were used as a model. After the treatment withBDNF, the subcellular distribution of tau protein was observed by immonocytochemistry;SH-SY5Y cell outgrowth was measured by Leica software; expression of tau protein wasdetected by Westernblot. These experiments were set to address the possible relationshipbetween the cellular distribution of tau protein and BDNF treatment during cell outgrowth.
Results：
Part I: TMT could induce abnormal morphology of dendritic spines
14DIV Primary cultured hippocampal neurons were treated by TMT for24h; cellviability was decreased significantly by CCK-8assay; while the application of BDNFtogether with TMT, cell viability does not increase significantly. Primary culturedhippocampal neurons were transfectd of GFP plasmid at7DIV and then were cultured to20days. Then it was treated by TMT and/or BDNF for24h. Confocal microscopy showedthat TMT treatment could cause the occurrence of ball-like morphological abnormalities ofdendritic spine. The application of BDNF could reduce the morphological abnormalities ofdendritic spine to some extent. BDNF and LiCl co-stimulation can also mimic this dendriticspine abnormality, which share great similarity of that treated by TMT. Westerbnlotshowed that BDNF treatment could both phosphorylated Akt and ERK in primary culturedhippocampal neurons (Figure2). Lithium alone does not seem to affect the phosphorylationstatus of both Akt and ERK. When adding the lithium together with BDNF, thephosphorylation of ERK induced by BDNF was not affected. But lithium inhibited thephoisphorylation of Akt induced by BDNF. TMT induced abnormal enlargement ofdendritic spine as well as that induced by BDNF and LiCl cotreatment might result from theimbalance of the cross-talk between ERK and Akt.
Part II: BDNF regulating morphological synaptic plasticity through tau protein
14day in vitro (DIV) hippocampal neurons were treated by BDNF for24h. Tauprotein expression was significantly increased and phosphorylation at Ser262wasdecreased after BDNF stimulation. Immunocytochemistry showed that colocalization of tauprotein and tubulin was enhanced by BDNF treatment. The increased tau protein expressionwas also consistent with the increase of dendritic spine density after BDNF treatment.Application of shRNA methods in cultured neurons at7days to down-regulate tau proteinexpression level, and then we observe at21day that hippocampal dendritic spine densitywas decreased significantly. And in hippocampal neurons whose tau protein was thedown-regulated by shRNA plasmid,24h BDNF stimulation could not increase the densityof dendritic spines of neurons.
Part III: BDNF regulation of tau protein phosphorylation and subcellulardistribution
By immunocytochemical method, we found that in undifferentiated SH-SY5Y cellslacking neurites, tau protein could form a sphere. In contrast, in SH-SY5Y cells differentiated by retinoic acid for5days, tau protein was distributed in the neuronalprocesses and the cell body. Through the Western blot detection method, we found thatretinoic acid also increased total tau protein levels and decreased tau protein levels ofSer262phosphorylation. The up-regulated expression of tau protein and tau proteinphosphorylation level of ser262reduction was associated with the neuronal processes (R=0.94and R=-0.98). When the primary cultured E18hippocampal neurons were treated withthe microtubule depolymerizing agent nocodazole, neuronal loss occurred and new tauprotein was transferred to the cell body. This process can be reversed the application ofBDNF to some extent.
Conclusion：
Based on the above results, we can draw the following conclusions that: TMTtreatment could cause the occurrence of ball-like morphological abnormalities of dendriticspine, which might be an important character of TMT neurotoxicity. The application ofBDNF showed potential protection against this damage. TMT induced abnormalenlargement of dendritic spine as well as that induced by BDNF and LiCl cotreatmentmight result from the imbalance of the cross-talk between ERK and Akt. BDNF canregulate the expression of tau protein in primary hippocampal neurons, and tau protein maybe involved in the signal pathway of BDNF regulating the synaptic plasticity, and theregulation effect may be achieved through regulation of tau protein expression andmodulation of tau protein microtubule stabilizing ability; tau protein Ser262sitephosphorylation, total tau protein expression and subcellular distribution of tau proteinchanges were closely related to the neuronal outgrowth; Our experiments provide newevidence for the neurotoxicity of TMT to hippocampal neurons, and also provide a newclue in revealing the role of tau in BDNF signaling pathway in regulating neuronaloutgrowth and dendritic spine morphology.
三氯甲基锡(Trimethyltin,TMT)是一种重要的职业危害毒物，也是一种重要的环境污染物。急性TMT暴露可引起多系统主要包括神经系统的损害。TMT作用于中枢神经系统，主要损伤作用机制为引起神经细胞凋亡，引起神经系统炎性反应，对神经组织造成氧化损伤等。TMT可以选择性地诱导大脑边缘系统，特别是海马神经元死亡，造成神经系统损伤效应。研究表明，BDNF在中枢神经系统的主要作用是调节海马神经突触可塑性。TMT暴露的大鼠大脑BDNF表达下调，而过表达BDNF的神经元具有拮抗TMT神经毒性的作用。但TMT对大脑神经元的损伤机制特别是对神经元树突棘的损伤研究还不清楚，并且BDNF拮抗TMT损伤发挥神经保护作用的机制尚待进一步研究。因此，本课题选取TMT及BDNF为研究内容，试图理解TMT对神经元的损伤作用机制及BDNF保护作用的分子机制，并为治疗和预防TMT职业暴露造成的神经元损伤提供思路。
突触可塑性指突触效率的功能性增强或降低，同时神经信号传递强度的变化伴随着神经元突触的结构变化。并且，BDNF参与调节活动依赖的树突棘发育及可塑性。近期研究表明BDNF可以作为成年脑中活动依赖性调节因子参与调控神经结构和功能变化。BDNF从树突分泌出来后，立即与神经营养因子受体TrkB结合，进而促进突触前神经递质的释放并且增加突触后蛋白的转录翻译水平。Tau蛋白主要表达于神经元树突轴，独立或与其他微管相关蛋白协同调节树突轴微管功能。在神经细胞中，tau蛋白与细胞膜相联系或与微管发生相互作用。Tau蛋白表达或者结构的变化可能影响其稳定微管蛋白的功能。在生理条件下，tau蛋白可能在不同的位点发生磷酸化改变，进而影响其稳定微管的功能。成熟神经元可以利用微管的动态性保持细胞体系的弹性，以适应神经网络发生的各种变化。
方法：
第一部分TMT对神经元毒性的观察
以原代培养的胚胎期18天海马神经元为模型，用TMT处理后，用CCK-8的方法观测BDNF对TMT的保护作用，观察TMT处理后神经元树突棘形态的影响以及BDNF的保护作用，并明确TMT对神经元树突棘毒性的特征；
第二部分BDNF对神经元突触和树突棘生长影响的观察
以原代培养的胚胎期18天海马神经元为模型，用BDNF处理，观察对原代培养海马神经元突触生长和树突棘形态的影响；利用质粒转染GFP或RFP标记原代海马神经元树突棘，细胞免疫荧光化学观测tau蛋白和微管的共定位情况，突触综合体测量BDNF处理后突触生长的变化，westernblot检测tau蛋白及其磷酸化变化，明确BDNF处理海马神经元后，神经元的形态突触可塑性的变化以及tau蛋白所起的作用；
第三部分BDNF对Tau蛋白磷酸化及细胞分布的观察
以RA分化的人神经母细胞瘤SH-SY5Y和原代培养的胚胎期18天海马神经元为模型，用BDNF处理后，采用细胞免疫荧光化学的方法观察tau蛋白的亚细胞分布情况，Leica软件测量SH-SY5Y细胞的突触生长情况，westernblot检测tau蛋白表达变化,明确tau蛋白亚细胞分布和BDNF处理后细胞的突触生长的关系；
结果：
第一部分TMT引起树突棘的异常形态改变
TMT处理体外培养14天的原代海马神经元24h，CCK-8检测细胞活力显著下降；加入BDNF与TMT共刺激后，CCK-8检测细胞活力无显著上升。原代海马神经元体外培养7天时转染GFP质粒，培养至20天，TMT和/或BDNF处理24h后固定细胞，共聚焦显微镜发现TMT处理后神经元树突棘出现异常圆形增大。加入BDNF处理后，树突棘的异常圆形增大有减少的趋势。BDNF与LiCl共刺激能够同样使神经元树突棘出现与TMT处理后高度相似的异常圆形增大。Westerbnlot实验结果表明，BDNF处理后可以同时在原代培养的海马神经元磷酸化Akt和ERK。而锂单独似乎不能影响Akt和ERK的磷酸化状态。当锂与BDNF同时作用时，BDNF诱导的ERK的磷酸化没有影响，但锂却抑制BDNF诱导的Akt磷酸化。TMT以及BDNF和LiCl联合作用产生的神经元树突棘异常增大可能与ERK与PI3K-Akt之间的cross-talk平衡被破坏有关。
第二部分BDNF通过tau蛋白调节突触和树突棘生长
BDNF处理体外培养14天的海马神经元24h，Tau蛋白的表达都显著升高，Ser262位点的磷酸化状态在BDNF刺激后具有下降的趋势。细胞免疫荧光化学实验也证明tau蛋白与微管蛋白在BDNF处理后的共定位得以增强。BDNF处理后tau蛋白的表达变化与树突棘密度的增加一致。运用shRNA技术在体外培养7天时下调tau蛋白表达水平后，培养至21天海马神经元树突棘密度显著下降。并且在shRNA下调tau蛋白的海马神经元中，24h BDNF刺激不能增加神经元的树突棘密度。
第三部分BDNF调节tau蛋白的磷酸化与亚细胞分布
通过免疫细胞化学方法，我们发现在未分化的缺乏神经突起的SH-SY5Y细胞中，tau蛋白形成一个球体。相反，在维甲酸诱导分化5天的SH-SY5Y细胞中，tau蛋白分散分布在神经细胞突起和胞体中。通过Western blot检测方法，我们发现维甲酸的处理也增加了总tau蛋白水平而降低tau蛋白Ser262磷酸化水平。Tau蛋白表达上调和tau蛋白ser262磷酸化水平的下调与神经细胞突起长度呈相关性(相关因子分别为r=0.94和r=-0.98)。当原E18海马神经元用微管解聚剂nocodazole处理后，新生的神经元突起丢失并且发生tau蛋白转移到胞体的现象。这种远离突起的过程可以被BDNF一定程度上逆转。
研究结论
基于以上研究结果，我们得出以下研究结论：TMT处理体外培养的海马神经元后发现神经元的树突棘出现异常的增大现象，可能是TMT的神经毒性表现。BDNF具有保护TMT树突棘损伤的潜力。TMT处理以及BDNF和LiCl联合作用产生的神经元树突棘异常增大可能与ERK与Akt之间的cross-talk平衡被破坏有关。BDNF能够调节原代海马神经元tau蛋白的表达,这样的调节具有剂量依赖关系和时效依赖关系。通过质粒转染原代培养海马神经元，下调tau蛋白表达，BDNF刺激神经元树突棘生长的现象被抑制，说明tau蛋白可能参与了BDNF调节神经元突触及树突棘生长的信号通路。进一步实验表明，BDNF调节树突棘可塑性的作用可能是通过调节tau蛋白的表达量进而影响tau蛋白稳定微管能力来实现的；tau蛋白Ser262位点的磷酸化水平，总tau蛋白的表达量以及tau蛋白的亚细胞分布变化与神经细胞突触生长的显著相关，tau蛋白的表达增加以及Ser262位点的去磷酸化可能以利于神经细胞突触的生长。本实验为TMT的神经毒性特别是对海马神经元树突棘的损伤提供新的证据，也揭示了BDNF可以通过tau蛋白调节突触以及树突棘生长发挥神经保护作用。
Background
TMT is an important occupation poison, and is a risk factor of environmental pollution.Acute TMT exposure could cause multi system including nerve system damage. The maindamage caused by TMT in the central nervous systemincludes apoptosis of nerve cells,neuronal inflammation and oxidative damage of the nervous tissue. TMT can selectivelyinduce the limbic system, especially caused the hippocampal neuronal death effect. BDNFplays a main role in regulating hippocampal synaptic plasticity in the central nervoussystem. Rat brain exposed to TMT showed reduced BDNF expression and the neurons overexpression of BDNFcould antagonist the neurotoxicity of TMT. But the mechanism ofTMT damage to the brain neurons especially the damage to neuronal dendritic spines isunclear, and the mechanisms of BDNF antagonist TMT damage effect remains to be furtherstudied.Therefore, this paper chooses BDNF and TMT as the research content, trying tounderstand TMT damage to the neural synaptic plasticity and the molecular mechanism ofBDNF protective effect, in order to provide clues for the treatment and prevention of TMToccupation exposure on synaptic plasticity damage.
Synaptic plasticity refers to the functional synaptic efficiency enhanced or reduced, atthe same time transmission of neural signal intensity changes accompanied by structuralchanges in neuronal synapse. Moreover, brain derived neurotrophic factor involved in thedevelopment and plasticity of dendritic spines of regulating activity dependent. Recentstudies show that BDNF can be used as the adult brain activity dependent regulation offactors involved in the changes of structure and function of regulating nerve. BDNFsecreted from the dendrites, immediately combined with neurotrophic factor receptor TrkB,and then promote the presynaptic neurotransmitter release and increase the level oftranscription and translation of the postsynaptic protein. Tau protein was mainly expressedin the neuronal dendritic shaft, independent or associated with other tubulin co regulation ofdendritic shaft microtubule function. In nerve cells, tau protein and cell membrane associated or interact with microtubules. Expression of Tau protein or structure may affectthe stability of microtubule protein function. Under physiological conditions, tau proteinphosphorylation changes may occur at different sites, thereby affecting its microtubulestabilizing function. Mature neurons can use dynamic microtubules maintain cell system, toadapt to the changes of neural network place.
Methods
Part I: To observe the neurotoxity of TMT
Primary cultures of embryonic day18hippocampal neurons were used as model. Afterthe treatment with TMT, the protective effect of BDNF was observed by CCK-8assay;neuronal dendritic spine morphology were observed after treatment with TMT and TMTplus BDNF.We would like to address the characteristic of TMT toxicity on dendritic spine.
Part II: To observe the effect of BDNF in the regulating synaptic plasticity
Primary cultured embryonic day18(E18) hippocampal neurons of embryonic day18was treated by BDNF, the effect of the hippocampal synaptic growth and dendritic spineswas observed; GFP, RFP plasmids were transfected into primary hippocampal neurons tolabel dendritic spines; colocalization of tau protein and the microtubules was examined byimmunocyochemistry; synaptic complex was measured after treatment with BDNF; tauprotein expression and phosphorylation was detected by Westernblot. These experimentsare set to investigate the role of tau protein in neuronal morphology changes in synapticplasticity of hippocampal neurons.
Part III: To observe the effect of BDNF on Tau phosphorylation and celldistribution
Retinoic acid (RA) differentiated human neuroblastoma SH-SY5Y and primary cultureof embryonic day18hippocampal neurons were used as a model. After the treatment withBDNF, the subcellular distribution of tau protein was observed by immonocytochemistry;SH-SY5Y cell outgrowth was measured by Leica software; expression of tau protein wasdetected by Westernblot. These experiments were set to address the possible relationshipbetween the cellular distribution of tau protein and BDNF treatment during cell outgrowth.
Results：
Part I: TMT could induce abnormal morphology of dendritic spines
14DIV Primary cultured hippocampal neurons were treated by TMT for24h; cellviability was decreased significantly by CCK-8assay; while the application of BDNFtogether with TMT, cell viability does not increase significantly. Primary culturedhippocampal neurons were transfectd of GFP plasmid at7DIV and then were cultured to20days. Then it was treated by TMT and/or BDNF for24h. Confocal microscopy showedthat TMT treatment could cause the occurrence of ball-like morphological abnormalities ofdendritic spine. The application of BDNF could reduce the morphological abnormalities ofdendritic spine to some extent. BDNF and LiCl co-stimulation can also mimic this dendriticspine abnormality, which share great similarity of that treated by TMT. Westerbnlotshowed that BDNF treatment could both phosphorylated Akt and ERK in primary culturedhippocampal neurons (Figure2). Lithium alone does not seem to affect the phosphorylationstatus of both Akt and ERK. When adding the lithium together with BDNF, thephosphorylation of ERK induced by BDNF was not affected. But lithium inhibited thephoisphorylation of Akt induced by BDNF. TMT induced abnormal enlargement ofdendritic spine as well as that induced by BDNF and LiCl cotreatment might result from theimbalance of the cross-talk between ERK and Akt.
Part II: BDNF regulating morphological synaptic plasticity through tau protein
14day in vitro (DIV) hippocampal neurons were treated by BDNF for24h. Tauprotein expression was significantly increased and phosphorylation at Ser262wasdecreased after BDNF stimulation. Immunocytochemistry showed that colocalization of tauprotein and tubulin was enhanced by BDNF treatment. The increased tau protein expressionwas also consistent with the increase of dendritic spine density after BDNF treatment.Application of shRNA methods in cultured neurons at7days to down-regulate tau proteinexpression level, and then we observe at21day that hippocampal dendritic spine densitywas decreased significantly. And in hippocampal neurons whose tau protein was thedown-regulated by shRNA plasmid,24h BDNF stimulation could not increase the densityof dendritic spines of neurons.
Part III: BDNF regulation of tau protein phosphorylation and subcellulardistribution
By immunocytochemical method, we found that in undifferentiated SH-SY5Y cellslacking neurites, tau protein could form a sphere. In contrast, in SH-SY5Y cells differentiated by retinoic acid for5days, tau protein was distributed in the neuronalprocesses and the cell body. Through the Western blot detection method, we found thatretinoic acid also increased total tau protein levels and decreased tau protein levels ofSer262phosphorylation. The up-regulated expression of tau protein and tau proteinphosphorylation level of ser262reduction was associated with the neuronal processes (R=0.94and R=-0.98). When the primary cultured E18hippocampal neurons were treated withthe microtubule depolymerizing agent nocodazole, neuronal loss occurred and new tauprotein was transferred to the cell body. This process can be reversed the application ofBDNF to some extent.
Conclusion：
Based on the above results, we can draw the following conclusions that: TMTtreatment could cause the occurrence of ball-like morphological abnormalities of dendriticspine, which might be an important character of TMT neurotoxicity. The application ofBDNF showed potential protection against this damage. TMT induced abnormalenlargement of dendritic spine as well as that induced by BDNF and LiCl cotreatmentmight result from the imbalance of the cross-talk between ERK and Akt. BDNF canregulate the expression of tau protein in primary hippocampal neurons, and tau protein maybe involved in the signal pathway of BDNF regulating the synaptic plasticity, and theregulation effect may be achieved through regulation of tau protein expression andmodulation of tau protein microtubule stabilizing ability; tau protein Ser262sitephosphorylation, total tau protein expression and subcellular distribution of tau proteinchanges were closely related to the neuronal outgrowth; Our experiments provide newevidence for the neurotoxicity of TMT to hippocampal neurons, and also provide a newclue in revealing the role of tau in BDNF signaling pathway in regulating neuronaloutgrowth and dendritic spine morphology.
引文
1Geloso MC, Corvino V, Michetti F Trimethyltin-induced hippocampal degeneration as a tool to investigateneurodegenerative processes. Neurochem Int.2011;58:729-738.
2Chang LW, Wenger GR, McMillan DE, Dyer RS Species and strain comparison of acute neurotoxic effects oftrimethyltin in mice and rats. Neurobehav Toxicol Teratol.1983;5:337-350.
3Harry GJ, Lefebvre d'Hellencourt C Dentate gyrus: alterations that occur with hippocampal injury. Neurotoxicology.2003;24:343-356.
4Balaban CD, O'Callaghan JP, Billingsley ML Trimethyltin-induced neuronal damage in the rat brain: comparativestudies using silver degeneration stains, immunocytochemistry and immunoassay for neuronotypic and gliotypic proteins.Neuroscience.1988;26:337-361.
1Andersson H, Wetmore C, Lindqvist E, Luthman J, Olson L Trimethyltin exposure in the rat induces delayed changesin brain-derived neurotrophic factor, fos and heat shock protein70. Neurotoxicology.1997;18:147-159.
2Casalbore P, Barone I, Felsani A, D'Agnano I, Michetti F, et al. Neural stem cells modified to express BDNFantagonize trimethyltin-induced neurotoxicity through PI3K/Akt and MAP kinase pathways. J Cell Physiol.2010;224:710-721.
3Greenberg ME, Xu B, Lu B, Hempstead BL New insights in the biology of BDNF synthesis and release: implicationsin CNS function. J Neurosci.2009;29:12764-12767.
Kang H, Schuman EM A requirement for local protein synthesis in neurotrophin-induced hippocampal synapticplasticity. Science.1996;273:1402-1406.
5Gonzalez-Billault C, Engelke M, Jimenez-Mateos EM, Wandosell F, Caceres A, et al. Participation of structuralmicrotubule-associated proteins (MAPs) in the development of neuronal polarity. J Neurosci Res.2002;67:713-719.
6Avila J, Lucas JJ, Perez M, Hernandez F Role of tau protein in both physiological and pathological conditions.Physiol Rev.2004;84:361-384.
7Hernandez F, Lucas JJ, Cuadros R, Avila J GSK-3dependent phosphoepitopes recognized by PHF-1and AT-8antibodies are present in different tau isoforms. Neurobiol Aging.2003;24:1087-1094.
Hoogenraad CC, Bradke F Control of neuronal polarity and plasticity--a renaissance for microtubules? Trends CellBiol.2009;19:669-676.
1Peng S, Wuu J, Mufson EJ, Fahnestock M Precursor form of brain-derived neurotrophic factor and maturebrain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer's disease. J Neurochem.2005;93:1412-1421.
2Fulga TA, Elson-Schwab I, Khurana V, Steinhilb ML, Spires TL, et al. Abnormal bundling and accumulation ofF-actin mediates tau-induced neuronal degeneration in vivo. Nat Cell Biol.2007;9:139-148.
3Brunden KR, Trojanowski JQ, Lee VM Advances in tau-focused drug discovery for Alzheimer's disease and relatedtauopathies. Nat Rev Drug Discov.2009;8:783-793.
4Wang JZ, Liu F Microtubule-associated protein tau in development, degeneration and protection of neurons. ProgNeurobiol.2008;85:148-175.
5Spires-Jones TL, Stoothoff WH, de Calignon A, Jones PB, Hyman BT Tau pathophysiology in neurodegeneration: atangled issue. Trends Neurosci.2009;32:150-159.
6Vega IE, Hamano T, Propost JA, Grenningloh G, Yen SH Taxol and tau overexpression induced calpain-dependentdegradation of the microtubule-destabilizing protein SCG10. Exp Neurol.2006;202:152-160.
7Niewiadomska G, Baksalerska-Pazera M, Riedel G Altered cellular distribution of phospho-tau proteins coincideswith impaired retrograde axonal transport in neurons of aged rats. Ann N Y Acad Sci.2005;1048:287-295.
8Zhang B, Maiti A, Shively S, Lakhani F, McDonald-Jones G, et al. Microtubule-binding drugs offset tau sequestrationby stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model. Proc Natl Acad Sci U S A.2005;102:227-231.
Rapoport M, Dawson HN, Binder LI, Vitek MP, Ferreira A Tau is essential to beta-amyloid-induced neurotoxicity.Proc Natl Acad Sci U S A.2002;99:6364-6369.
1Morris M, Maeda S, Vossel K, Mucke L The many faces of tau. Neuron.2011;70:410-426.
2Wolfe MS Tau mutations in neurodegenerative diseases. J Biol Chem.2009;284:6021-6025.
3Papanikolopoulou K, Kosmidis S, Grammenoudi S, Skoulakis EM Phosphorylation differentiates tau-dependentneuronal toxicity and dysfunction. Biochem Soc Trans.2010;38:981-987.
4Liu L, Drouet V, Wu JW, Witter MP, Small SA, et al. Trans-synaptic spread of tau pathology in vivo. PLoS One.2012;7: e31302.
Nagahara AH, Tuszynski MH Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat RevDrug Discov.2011;10:209-219.
1Figiel I, Fiedorowicz A Trimethyltin-evoked neuronal apoptosis and glia response in mixed cultures of rathippocampal dentate gyrus: a new model for the study of the cell type-specific influence of neurotoxins. Neurotoxicology.2002;23:77-86.
1Aksamitiene E, Kiyatkin A, Kholodenko BN Cross-talk between mitogenic Ras/MAPK and survival PI3K/Aktpathways: a fine balance. Biochem Soc Trans.2012;40:139-146.
2Qing Y, Liang Y, Du Q, Fan P, Xu H, et al. Apoptosis induced by trimethyltin chloride in human neuroblastoma cellsSY5Y is regulated by a balance and cross-talk between NF-kappaB and MAPKs signaling pathways. Arch Toxicol.87:1273-1285.
3Tran HY, Shin EJ, Saito K, Nguyen XK, Chung YH, et al. Protective potential of IL-6against trimethyltin-inducedneurotoxicity in vivo. Free Radic Biol Med.52:1159-1174.
4Dopp E, Hartmann LM, von Recklinghausen U, Florea AM, Rabieh S, et al. The cyto-and genotoxicity of organotincompounds is dependent on the cellular uptake capability. Toxicology.2007;232:226-234.
5Piacentini R, Gangitano C, Ceccariglia S, Del Fa A, Azzena GB, et al. Dysregulation of intracellular calciumhomeostasis is responsible for neuronal death in an experimental model of selective hippocampal degeneration inducedby trimethyltin. J Neurochem.2008;105:2109-2121.
Zhang L, Li L, Prabhakaran K, Borowitz JL, Isom GE Trimethyltin-induced apoptosis is associated with upregulationof inducible nitric oxide synthase and Bax in a hippocampal cell line. Toxicol Appl Pharmacol.2006;216:34-43.
1Duchen MR Mitochondria, calcium-dependent neuronal death and neurodegenerative disease. Pflugers Arch.464:111-121.
2Zhang L, Li L, Prabhakaran K, Borowitz JL, Isom GE Trimethyltin-induced apoptosis is associated with upregulationof inducible nitric oxide synthase and Bax in a hippocampal cell line. Toxicol Appl Pharmacol.2006;216:34-43.
3Cai J, Wang M, Li B, Wang C, Chen Y, et al. Apoptotic and necrotic action mechanisms of trimethyltin in humanhepatoma G2(HepG2) cells. Chem Res Toxicol.2009;22:1582-1587.
4Geloso MC, Vercelli A, Corvino V, Repici M, Boca M, et al. Cyclooxygenase-2and caspase3expression intrimethyltin-induced apoptosis in the mouse hippocampus. Exp Neurol.2002;175:152-160.
5Minghetti L Role of inflammation in neurodegenerative diseases. Curr Opin Neurol.2005;18:315-321.
Geloso MC, Corvino V, Michetti F Trimethyltin-induced hippocampal degeneration as a tool to investigateneurodegenerative processes. Neurochem Int.2011;58:729-738.
1Lu B, Nagappan G, Guan X, Nathan PJ, Wren P BDNF-based synaptic repair as a disease-modifying strategy forneurodegenerative diseases. Nat Rev Neurosci.2013;14:401-416.
2Casalbore P, Barone I, Felsani A, D'Agnano I, Michetti F, et al. Neural stem cells modified to express BDNFantagonize trimethyltin-induced neurotoxicity through PI3K/Akt and MAP kinase pathways. J Cell Physiol.2010;224:710-721.
Andersson H, Wetmore C, Lindqvist E, Luthman J, Olson L Trimethyltin exposure in the rat induces delayed changesin brain-derived neurotrophic factor, fos and heat shock protein70. Neurotoxicology.1997;18:147-159.
4Koda T, Kuroda Y, Imai H Protective effect of rutin against spatial memory impairment induced by trimethyltin inrats. Nutr Res.2008;28:629-634.
5Koda T, Kuroda Y, Imai H Rutin supplementation in the diet has protective effects against toxicant-inducedhippocampal injury by suppression of microglial activation and pro-inflammatory cytokines: protective effect of rutinagainst toxicant-induced hippocampal injury. Cell Mol Neurobiol.2009;29:523-531.
6Kim JK, Bae H, Kim MJ, Choi SJ, Cho HY, et al. Inhibitory effect of Poncirus trifoliate on acetylcholinesterase andattenuating activity against trimethyltin-induced learning and memory impairment. Biosci Biotechnol Biochem.2009;73:1105-1112.
1Kim JK, Bae H, Kim MJ, Choi SJ, Cho HY, et al. Inhibitory effect of Poncirus trifoliate on acetylcholinesterase andattenuating activity against trimethyltin-induced learning and memory impairment. Biosci Biotechnol Biochem.2009;73:1105-1112.
2Czlonkowska A, Kurkowska-Jastrzebska I Inflammation and gliosis in neurological diseases--clinical implications. JNeuroimmunol.2011;231:78-85.
Funk JA, Gohlke J, Kraft AD, McPherson CA, Collins JB, et al. Voluntary exercise protects hippocampal neuronsfrom trimethyltin injury: possible role of interleukin-6to modulate tumor necrosis factor receptor-mediated neurotoxicity.Brain Behav Immun.2011;25:1063-1077.
4Shuto M, Higuchi K, Sugiyama C, Yoneyama M, Kuramoto N, et al. Endogenous and exogenous glucocorticoidsprevent trimethyltin from causing neuronal degeneration of the mouse brain in vivo: involvement of oxidative stresspathways. J Pharmacol Sci.2009;110:424-436.
5Shin EJ, Suh SK, Lim YK, Jhoo WK, Hjelle OP, et al. Ascorbate attenuates trimethyltin-induced oxidative burdenand neuronal degeneration in the rat hippocampus by maintaining glutathione homeostasis. Neuroscience.2005;133:715-727.
6Arancio O, Chao MV Neurotrophins, synaptic plasticity and dementia. Curr Opin Neurobiol.2007;17:325-330.
1Bhatt DH, Zhang S, Gan WB Dendritic spine dynamics. Annu Rev Physiol.2009;71:261-282.
Polydoro M, Acker CM, Duff K, Castillo PE, Davies P Age-dependent impairment of cognitive and synaptic functionin the htau mouse model of tau pathology. J Neurosci.2009;29:10741-10749.
3Dopp E, Hartmann LM, von Recklinghausen U, Florea AM, Rabieh S, et al. The cyto-and genotoxicity of organotincompounds is dependent on the cellular uptake capability. Toxicology.2007;232:226-234.
4Hemmings BA Akt signaling: linking membrane events to life and death decisions. Science.1997;275:628-630.
5Impey S, Obrietan K, Storm DR Making new connections: role of ERK/MAP kinase signaling in neuronal plasticity.Neuron.1999;23:11-14.
6Aksamitiene E, Kiyatkin A, Kholodenko BN Cross-talk between mitogenic Ras/MAPK and survival PI3K/Aktpathways: a fine balance. Biochem Soc Trans.2012;40:139-146.
7Dent P Crosstalk between ERK, AKT, and cell survival. Cancer Biol Ther.2014;15:245-246.
1Gonzalez-Billault C, Engelke M, Jimenez-Mateos EM, Wandosell F, Caceres A, et al. Participation of structuralmicrotubule-associated proteins (MAPs) in the development of neuronal polarity. J Neurosci Res.2002;67:713-719.
2Caceres A, Kosik KS Inhibition of neurite polarity by tau antisense oligonucleotides in primary cerebellar neurons.Nature.1990;343:461-463.
Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW A protein factor essential for microtubule assembly. ProcNatl Acad Sci U S A.1975;72:1858-1862.
1Thies E, Mandelkow EM Missorting of tau in neurons causes degeneration of synapses that can be rescued by thekinase MARK2/Par-1. J Neurosci.2007;27:2896-2907.
Dickstein DL, Brautigam H, Stockton SD, Jr., Schmeidler J, Hof PR Changes in dendritic complexity and spinemorphology in transgenic mice expressing human wild-type tau. Brain Struct Funct.2010;214:161-179.
3Eckermann K, Mocanu MM, Khlistunova I, Biernat J, Nissen A, et al. The beta-propensity of Tau determinesaggregation and synaptic loss in inducible mouse models of tauopathy. J Biol Chem.2007;282:31755-31765.
4Jaworski J, Kapitein LC, Gouveia SM, Dortland BR, Wulf PS, et al. Dynamic microtubules regulate dendritic spinemorphology and synaptic plasticity. Neuron.2009;61:85-100.
5Hoogenraad CC, Bradke F Control of neuronal polarity and plasticity--a renaissance for microtubules? Trends CellBiol.2009;19:669-676.
Erturk A, Hellal F, Enes J, Bradke F Disorganized microtubules underlie the formation of retraction bulbs and thefailure of axonal regeneration. J Neurosci.2007;27:9169-9180.
1Yuan J, Yankner BA Apoptosis in the nervous system. Nature.2000;407:802-809.
2Drewes G, Trinczek B, Illenberger S, Biernat J, Schmitt-Ulms G, et al. Microtubule-associated protein/microtubuleaffinity-regulating kinase (p110mark). A novel protein kinase that regulates tau-microtubule interactions and dynamicinstability by phosphorylation at the Alzheimer-specific site serine262. J Biol Chem.1995;270:7679-7688.
3Utton MA, Vandecandelaere A, Wagner U, Reynolds CH, Gibb GM, et al. Phosphorylation of tau by glycogen
synthase kinase3beta affects the ability of tau to promote microtubule self-assembly. Biochem J.1997;323(Pt3):741-747.
4Biernat J, Gustke N, Drewes G, Mandelkow EM, Mandelkow E Phosphorylation of Ser262strongly reduces bindingof tau to microtubules: distinction between PHF-like immunoreactivity and microtubule binding. Neuron.1993;11:153-163.
5Polydoro M, Acker CM, Duff K, Castillo PE, Davies P Age-dependent impairment of cognitive and synaptic functionin the htau mouse model of tau pathology. J Neurosci.2009;29:10741-10749.
6Peng S, Wuu J, Mufson EJ, Fahnestock M Precursor form of brain-derived neurotrophic factor and maturebrain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer's disease. J Neurochem.2005;93:1412-1421.
1Johnson GV, Stoothoff WH Tau phosphorylation in neuronal cell function and dysfunction. J Cell Sci.2004;117:5721-5729.
Liu F, Li B, Tung EJ, Grundke-Iqbal I, Iqbal K, et al. Site-specific effects of tau phosphorylation on its microtubuleassembly activity and self-aggregation. Eur J Neurosci.2007;26:3429-3436.
3Mondragon-Rodriguez S, Mena R, Binder LI, Smith MA, Perry G, et al. Conformational changes and cleavage of tauin Pick bodies parallel the early processing of tau found in Alzheimer pathology. Neuropathol Appl Neurobiol.2008;34:62-75.
4Mondragon-Rodriguez S, Trillaud-Doppia E, Dudilot A, Bourgeois C, Lauzon M, et al. Interaction of endogenous tauprotein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation. J Biol Chem.2012;287:32040-32053.
Ho YS, Yang X, Lau JC, Hung CH, Wuwongse S, et al. Endoplasmic reticulum stress induces tau pathology andforms a vicious cycle: implication in Alzheimer's disease pathogenesis. J Alzheimers Dis.2012;28:839-854.
1Kosik KS, Kowall NW, McKee A Along the way to a neurofibrillary tangle: a look at the structure of tau. Ann Med.1989;21:109-112.
1Greenberg ME, Xu B, Lu B, Hempstead BL New insights in the biology of BDNF synthesis and release: implicationsin CNS function. J Neurosci.2009;29:12764-12767.
2Lu B BDNF and activity-dependent synaptic modulation. Learn Mem.2003;10:86-98.
1Drewes G, Trinczek B, Illenberger S, Biernat J, Schmitt-Ulms G, et al. Microtubule-associated protein/microtubuleaffinity-regulating kinase (p110mark). A novel protein kinase that regulates tau-microtubule interactions and dynamicinstability by phosphorylation at the Alzheimer-specific site serine262. J Biol Chem.1995;270:7679-7688.
2Haque N, Tanaka T, Iqbal K, Grundke-Iqbal I Regulation of expression, phosphorylation and biological activity of tauduring differentiation in SY5Y cells. Brain Res.1999;838:69-77.
3Avila J, Lucas JJ, Perez M, Hernandez F Role of tau protein in both physiological and pathological conditions.Physiol Rev.2004;84:361-384.
Hoogenraad CC, Bradke F Control of neuronal polarity and plasticity--a renaissance for microtubules? Trends CellBiol.2009;19:669-676.
1Morris M, Maeda S, Vossel K, Mucke L The many faces of tau. Neuron.2011;70:410-426.
2Whiteman IT, Minamide LS, Goh de L, Bamburg JR, Goldsbury C Rapid changes in phospho-MAP/tau epitopesduring neuronal stress: cofilin-actin rods primarily recruit microtubule binding domain epitopes. PLoS One.2011;6:e20878.
1Park H, Poo MM Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci.2013;14:27-23.
Cohen-Cory S, Fraser SE Effects of brain-derived neurotrophic factor on optic axon branching and remodelling invivo. Nature.1995;378:192-196.
3Ji Y, Lu Y, Yang F, Shen W, Tang TT, et al. Acute and gradual increases in BDNF concentration elicit distinctsignaling and functions in neurons. Nat Neurosci.2010;13:302-309.
4Tyler WJ, Pozzo-Miller L Miniature synaptic transmission and BDNF modulate dendritic spine growth and form inrat CA1neurones. J Physiol.2003;553:497-509.
5Horch HW, Kruttgen A, Portbury SD, Katz LC Destabilization of cortical dendrites and spines by BDNF. Neuron.1999;23:353-364.
Brandt R, Leger J, Lee G Interaction of tau with the neural plasma membrane mediated by tau's amino-terminalprojection domain. J Cell Biol.1995;131:1327-1340.
1Vasquez RJ, Howell B, Yvon AM, Wadsworth P, Cassimeris L Nanomolar concentrations of nocodazole alter2microtubule dynamic instability in vivo and in vitro. Mol Biol Cell.1997;8:973-985.
Zempel H, Thies E, Mandelkow E, Mandelkow EM Abeta oligomers cause localized Ca(2+) elevation, missorting ofendogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J Neurosci.2010;30:11938-11950.
3Lu B, Nagappan G, Guan X, Nathan PJ, Wren P BDNF-based synaptic repair as a disease-modifying strategy forneurodegenerative diseases. Nat Rev Neurosci.2013;14:401-416.
4Ballatore C, Lee VM, Trojanowski JQ Tau-mediated neurodegeneration in Alzheimer's disease and related disorders.Nat Rev Neurosci.2007;8:663-672.
5Drubin D, Kobayashi S, Kellogg D, Kirschner M Regulation of microtubule protein levels during cellularmorphogenesis in nerve growth factor-treated PC12cells. J Cell Biol.1988;106:1583-1591.
6David DC, Layfield R, Serpell L, Narain Y, Goedert M, et al. Proteasomal degradation of tau protein. J Neurochem.2002;83:176-185.
7Jinwal UK, Trotter JH, Abisambra JF, Koren J,3rd, Lawson LY, et al. The Hsp90kinase co-chaperone Cdc37regulates tau stability and phosphorylation dynamics. J Biol Chem.2011;286:16976-16983.
8Yoshizaki C, Tsukane M, Yamauchi T Overexpression of tau leads to the stimulation of neurite outgrowth, theactivation of caspase3activity, and accumulation and phosphorylation of tau in neuroblastoma cells on cAMP treatment.Neurosci Res.2004;49:363-371.
Sultan A, Nesslany F, Violet M, Begard S, Loyens A, et al. Nuclear tau, a key player in neuronal DNA protection. JBiol Chem.2011;286:4566-4575.
1Strittmatter WJ, Saunders AM, Goedert M, Weisgraber KH, Dong LM, et al. Isoform-specific interactions ofapolipoprotein E with microtubule-associated protein tau: implications for Alzheimer disease. Proc Natl Acad Sci U S A.1994;91:11183-11186.
2Bhaskar K, Yen SH, Lee G Disease-related modifications in tau affect the interaction between Fyn and Tau. J BiolChem.2005;280:35119-35125.
3Dawson HN, Cantillana V, Jansen M, Wang H, Vitek MP, et al. Loss of tau elicits axonal degeneration in a mousemodel of Alzheimer's disease. Neuroscience.2010;169:516-531.
4Morris M, Maeda S, Vossel K, Mucke L The many faces of tau. Neuron.2011;70:410-426.
5Jin M, Shepardson N, Yang T, Chen G, Walsh D, et al. Soluble amyloid beta-protein dimers isolated from Alzheimercortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc Natl Acad Sci U S A.2011;108:5819-5824.
6Zempel H, Thies E, Mandelkow E, Mandelkow EM Abeta oligomers cause localized Ca(2+) elevation, missorting ofendogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J Neurosci.2010;30:11938-11950.
Planel E, Tatebayashi Y, Miyasaka T, Liu L, Wang L, et al. Insulin dysfunction induces in vivo tauhyperphosphorylation through distinct mechanisms. J Neurosci.2007;27:13635-13648.
8Miao Y, Chen J, Zhang Q, Sun A Deletion of tau attenuates heat shock-induced injury in cultured cortical neurons. JNeurosci Res.2010;88:102-110.
9Spires-Jones TL, Stoothoff WH, de Calignon A, Jones PB, Hyman BT Tau pathophysiology in neurodegeneration: atangled issue. Trends Neurosci.2009;32:150-159.
10Noble W, Pooler AM, Hanger DP Advances in tau-based drug discovery. Expert Opin Drug Discov.2011;6:797-810.
Gordon D, Kidd GJ, Smith R Antisense suppression of tau in cultured rat oligodendrocytes inhibits processformation. J Neurosci Res.2008;86:2591-2601.
1Caccamo A, Maldonado MA, Bokov AF, Majumder S, Oddo S CBP gene transfer increases BDNF levels andameliorates learning and memory deficits in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A.2010;107:22687-22692.
2Blurton-Jones M, Kitazawa M, Martinez-Coria H, Castello NA, Muller FJ, et al. Neural stem cells improve cognitionvia BDNF in a transgenic model of Alzheimer disease. Proc Natl Acad Sci U S A.2009;106:13594-13599.
3Encinas M, Iglesias M, Liu Y, Wang H, Muhaisen A, et al. Sequential treatment of SH-SY5Y cells with retinoic acidand brain-derived neurotrophic factor gives rise to fully differentiated, neurotrophic factor-dependent, human neuron-likecells. J Neurochem.2000;75:991-1003.
4Jamsa A, Hasslund K, Cowburn RF, Backstrom A, Vasange M The retinoic acid and brain-derived neurotrophic factordifferentiated SH-SY5Y cell line as a model for Alzheimer's disease-like tau phosphorylation. Biochem Biophys ResCommun.2004;319:993-1000.
5Haque N, Tanaka T, Iqbal K, Grundke-Iqbal I Regulation of expression, phosphorylation and biological activity of tauduring differentiation in SY5Y cells. Brain Res.1999;838:69-77.
6Biernat J, Gustke N, Drewes G, Mandelkow EM, Mandelkow E Phosphorylation of Ser262strongly reduces bindingof tau to microtubules: distinction between PHF-like immunoreactivity and microtubule binding. Neuron.1993;11:153-163.
1Besser R, Kramer G, Thumler R, Bohl J, Gutmann L, et al. Acute trimethyltin limbic-cerebellar syndrome. Neurology.1987;37:945-950.
2Balaban CD, O'Callaghan JP, Billingsley ML Trimethyltin-induced neuronal damage in the rat brain: comparativestudies using silver degeneration stains, immunocytochemistry and immunoassay for neuronotypic and gliotypic proteins.Neuroscience.1988;26:337-361.
3Chang LW, Dyer RS A time-course study of trimethyltin induced neuropathology in rats. Neurobehav Toxicol Teratol.1983;5:443-459.
4Ishikawa K, Kubo T, Shibanoki S, Matsumoto A, Hata H, et al. Hippocampal degeneration inducing impairment oflearning in rats: model of dementia? Behav Brain Res.1997;83:39-44.
5Ishikura N, Tsunashima K, Watanabe K, Nishimura T, Minabe Y, et al. Neuropeptide Y and somatostatin participatedifferently in the seizure-generating mechanisms following trimethyltin-induced hippocampal damage. Neurosci Res.2002;44:237-248.
6Nilsberth C, Kostyszyn B, Luthman J Changes in APP, PS1and other factors related to Alzheimer's diseasepathophysiology after trimethyltin-induced brain lesion in the rat. Neurotox Res.2002;4:625-636.
Boyer IJ Toxicity of dibutyltin, tributyltin and other organotin compounds to humans and to experimental animals.Toxicology.1989;55:253-298.
8Borghi V, Porte C Organotin pollution in deep-sea fish from the northwestern Mediterranean. Environ Sci Technol.2002;36:4224-4228.
9Chang LW The neurotoxicology and pathology of organomercury, organolead, and organotin. J Toxicol Sci.1990;15Suppl4:125-151.
10Yoo CI, Kim Y, Jeong KS, Sim CS, Choy N, et al. A case of acute organotin poisoning. J Occup Health.2007;49:305-310.
Holloway LN, Pannell KH, Whalen MM Effects of a series of triorganotins on ATP levels in human natural killercells. Environ Toxicol Pharmacol.2008;25:43-50.
1Fortemps E, Amand G, Bomboir A, Lauwerys R, Laterre EC Trimethyltin poisoning. Report of two cases. Int ArchOccup Environ Health.1978;41:1-6.
2Ross WD, Emmett EA, Steiner J, Tureen R Neurotoxic effects of occupational exposure to organotins. Am JPsychiatry.1981;138:1092-1095.
3Kreyberg S, Torvik A, Bjorneboe A, Wiik-Larsen W, Jacobsen D Trimethyltin poisoning: report of a case withpostmortem examination. Clin Neuropathol.1992;11:256-259.
4Ghosh BB, Talukder G, Sharma A Frequency of chromosome aberrations induced by trimethyltin chloride in humanperipheral blood lymphocytes in vitro: related to age of donors. Mech Ageing Dev.1991;57:125-137.
5Gomez FD, Apodaca P, Holloway LN, Pannell KH, Whalen MM Effect of a series of triorganotins on the immunefunction of human natural killer cells. Environ Toxicol Pharmacol.2007;23:18-24.
6Ohno H, Suzuki M, Nakashima S, Aoyama T, Mitani K [Determination of organotin compounds in plastic productsby GC/MS after ethyl derivatization with sodium tetraethylborate]. Shokuhin Eiseigaku Zasshi.2002;43:208-214.
7Fent K Ecotoxicology of organotin compounds. Crit Rev Toxicol.1996;26:1-117.
8Holloway LN, Pannell KH, Whalen MM Effects of a series of triorganotins on ATP levels in human natural killercells. Environ Toxicol Pharmacol.2008;25:43-50.
9Teuten EL, Saquing JM, Knappe DR, Barlaz MA, Jonsson S, et al. Transport and release of chemicals from plastics tothe environment and to wildlife. Philos Trans R Soc Lond B Biol Sci.2009;364:2027-2045.
10Vajda FJ Neuroprotection and neurodegenerative disease. J Clin Neurosci.2002;9:4-8.
11Mattson MP Glutamate and neurotrophic factors in neuronal plasticity and disease. Ann N Y Acad Sci.2008;1144:97-112.
12Minghetti L Role of inflammation in neurodegenerative diseases. Curr Opin Neurol.2005;18:315-321.
1Parent JM Injury-induced neurogenesis in the adult mammalian brain. Neuroscientist.2003;9:261-272.
2Geloso MC, Corvino V, Michetti F Trimethyltin-induced hippocampal degeneration as a tool to investigateneurodegenerative processes. Neurochem Int.2011;58:729-738.
3Chang LW, Wenger GR, McMillan DE, Dyer RS Species and strain comparison of acute neurotoxic effects oftrimethyltin in mice and rats. Neurobehav Toxicol Teratol.1983;5:337-350.
4Harry GJ, Lefebvre d'Hellencourt C Dentate gyrus: alterations that occur with hippocampal injury. Neurotoxicology.2003;24:343-356.
5Geloso MC, Corvino V, Michetti F Trimethyltin-induced hippocampal degeneration as a tool to investigateneurodegenerative processes. Neurochem Int.2011;58:729-738.
6Balaban CD, O'Callaghan JP, Billingsley ML Trimethyltin-induced neuronal damage in the rat brain: comparativestudies using silver degeneration stains, immunocytochemistry and immunoassay for neuronotypic and gliotypic proteins.Neuroscience.1988;26:337-361.
Kreyberg S, Torvik A, Bjorneboe A, Wiik-Larsen W, Jacobsen D Trimethyltin poisoning: report of a case withpostmortem examination. Clin Neuropathol.1992;11:256-259.
1Misiti F, Orsini F, Clementi ME, Lattanzi W, Giardina B, et al. Mitochondrial oxygen consumption inhibitionimportance for TMT-dependent cell death in undifferentiated PC12cells. Neurochem Int.2008;52:1092-1099.
2Billingsley ML, Yun J, Reese BE, Davidson CE, Buck-Koehntop BA, et al. Functional and structural properties ofstannin: roles in cellular growth, selective toxicity, and mitochondrial responses to injury. J Cell Biochem.2006;98:243-250.
3Piacentini R, Gangitano C, Ceccariglia S, Del Fa A, Azzena GB, et al. Dysregulation of intracellular calciumhomeostasis is responsible for neuronal death in an experimental model of selective hippocampal degeneration inducedby trimethyltin. J Neurochem.2008;105:2109-2121.
4Ceccariglia S, D'Altocolle A, Del Fa A, Pizzolante F, Caccia E, et al. Cathepsin D plays a crucial role in thetrimethyltin-induced hippocampal neurodegeneration process. Neuroscience.174:160-170.
5Casalbore P, Barone I, Felsani A, D'Agnano I, Michetti F, et al. Neural stem cells modified to express BDNFantagonize trimethyltin-induced neurotoxicity through PI3K/Akt and MAP kinase pathways. J Cell Physiol.2010;224:710-721.
6Andersson H, Wetmore C, Lindqvist E, Luthman J, Olson L Trimethyltin exposure in the rat induces delayed changesin brain-derived neurotrophic factor, fos and heat shock protein70. Neurotoxicology.1997;18:147-159.
7Cohen-Cory S, Fraser SE Effects of brain-derived neurotrophic factor on optic axon branching and remodelling invivo. Nature.1995;378:192-196.
8McAllister AK, Lo DC, Katz LC Neurotrophins regulate dendritic growth in developing visual cortex. Neuron.1995;15:791-803.
Ji Y, Lu Y, Yang F, Shen W, Tang TT, et al. Acute and gradual increases in BDNF concentration elicit distinctsignaling and functions in neurons. Nat Neurosci.2010;13:302-309.
1Tartaglia N, Du J, Tyler WJ, Neale E, Pozzo-Miller L, et al. Protein synthesis-dependent and-independent regulationof hippocampal synapses by brain-derived neurotrophic factor. J Biol Chem.2001;276:37585-37593.
2Horch HW, Kruttgen A, Portbury SD, Katz LC Destabilization of cortical dendrites and spines by BDNF. Neuron.1999;23:353-364.
3Pozzo-Miller LD, Gottschalk W, Zhang L, McDermott K, Du J, et al. Impairments in high-frequency transmission,synaptic vesicle docking, and synaptic protein distribution in the hippocampus of BDNF knockout mice. J Neurosci.1999;19:4972-4983.
4Otal R, Martinez A, Soriano E Lack of TrkB and TrkC signaling alters the synaptogenesis and maturation of mossyfiber terminals in the hippocampus. Cell Tissue Res.2005;319:349-358.
5Aguado F, Carmona MA, Pozas E, Aguilo A, Martinez-Guijarro FJ, et al. BDNF regulates spontaneous correlatedactivity at early developmental stages by increasing synaptogenesis and expression of the K+/Cl-co-transporter KCC2.Development.2003;130:1267-1280.
6Singh B, Henneberger C, Betances D, Arevalo MA, Rodriguez-Tebar A, et al. Altered balance ofglutamatergic/GABAergic synaptic input and associated changes in dendrite morphology after BDNF expression inBDNF-deficient hippocampal neurons. J Neurosci.2006;26:7189-7200.
7Tanaka J, Horiike Y, Matsuzaki M, Miyazaki T, Ellis-Davies GC, et al. Protein synthesis and neurotrophin-dependentstructural plasticity of single dendritic spines. Science.2008;319:1683-1687.
8Ma YL, Wang HL, Wu HC, Wei CL, Lee EH Brain-derived neurotrophic factor antisense oligonucleotide impairsmemory retention and inhibits long-term potentiation in rats. Neuroscience.1998;82:957-967.
Alonso M, Vianna MR, Izquierdo I, Medina JH Signaling mechanisms mediating BDNF modulation of memoryformation in vivo in the hippocampus. Cell Mol Neurobiol.2002;22:663-674.
1Nagahara AH, Tuszynski MH Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat RevDrug Discov.2011;10:209-219.
Kemppainen S, Rantamaki T, Jeronimo-Santos A, Lavasseur G, Autio H, et al. Impaired TrkB receptor signalingcontributes to memory impairment in APP/PS1mice. Neurobiol Aging.2012;33:1122e1123-1139.
3Nagahara AH, Merrill DA, Coppola G, Tsukada S, Schroeder BE, et al. Neuroprotective effects of brain-derivedneurotrophic factor in rodent and primate models of Alzheimer's disease. Nat Med.2009;15:331-337.
4Minghetti L Role of inflammation in neurodegenerative diseases. Curr Opin Neurol.2005;18:315-321.
5Kraft AD, McPherson CA, Harry GJ Heterogeneity of microglia and TNF signaling as determinants for neuronaldeath or survival. Neurotoxicology.2009;30:785-793.
6Tran HY, Shin EJ, Saito K, Nguyen XK, Chung YH, et al. Protective potential of IL-6against trimethyltin-inducedneurotoxicity in vivo. Free Radic Biol Med.2012;52:1159-1174.
7Jean Harry G, Bruccoleri A, Lefebvre d'Hellencourt C Differential modulation of hippocampal chemical-inducedinjury response by ebselen, pentoxifylline, and TNFalpha-, IL-1alpha-, and IL-6-neutralizing antibodies. J Neurosci Res.2003;73:526-536.
8Brabeck C, Michetti F, Geloso MC, Corvino V, Goezalan F, et al. Expression of EMAP-II by activatedmonocytes/microglial cells in different regions of the rat hippocampus after trimethyltin-induced brain damage. ExpNeurol.2002;177:341-346.
9Little AR, Miller DB, Li S, Kashon ML, O'Callaghan JP Trimethyltin-induced neurotoxicity: gene expressionpathway analysis, q-RT-PCR and immunoblotting reveal early effects associated with hippocampal damage and gliosis.Neurotoxicol Teratol.2012;34:72-82.
1Liu Y, Imai H, Sadamatsu M, Tsunashima K, Kato N Cytokines participate in neuronal death induced by trimethyltin
2in the rat hippocampus via type II glucocorticoid receptors. Neurosci Res.2005;51:319-327.Corvino V, Marchese E, Zarkovic N, Zarkovic K, Cindric M, et al. Distribution and time-course of4-hydroxynonenal,heat shock protein110/105family members and cyclooxygenase-2expression in the hippocampus of rat duringtrimethyltin-induced neurodegeneration. Neurochem Res.2011;36:1490-1500.
3Allaman I, Belanger M, Magistretti PJ Astrocyte-neuron metabolic relationships: for better and for worse. TrendsNeurosci.2011;34:76-87.
4Zarkovic N, Zarkovic K, Schaur RJ, Stolc S, Schlag G, et al.4-Hydroxynonenal as a second messenger of freeradicals and growth modifying factor. Life Sci.1999;65:1901-1904.
56Coyle JT, Puttfarcken P Oxidative stress, glutamate, and neurodegenerative disorders. Science.1993;262:689-695.Schulz JB, Lindenau J, Seyfried J, Dichgans J Glutathione, oxidative stress and neurodegeneration. Eur J Biochem.2000;267:4904-4911.
7Ali SF, LeBel CP, Bondy SC Reactive oxygen species formation as a biomarker of methylmercury and trimethyltinneurotoxicity. Neurotoxicology.1992;13:637-648.
8Shin EJ, Suh SK, Lim YK, Jhoo WK, Hjelle OP, et al. Ascorbate attenuates trimethyltin-induced oxidative burdenand neuronal degeneration in the rat hippocampus by maintaining glutathione homeostasis. Neuroscience.2005;133:715-727.
9Haddad el B, McCluskie K, Birrell MA, Dabrowski D, Pecoraro M, et al. Differential effects of ebselen on neutrophilrecruitment, chemokine, and inflammatory mediator expression in a rat model of lipopolysaccharide-induced pulmonaryinflammation. J Immunol.2002;169:974-982.
1Haddad el B, McCluskie K, Birrell MA, Dabrowski D, Pecoraro M, et al. Differential effects of ebselen on neutrophilrecruitment, chemokine, and inflammatory mediator expression in a rat model of lipopolysaccharide-induced pulmonaryinflammation. J Immunol.2002;169:974-982.
2Koizumi H, Fujisawa H, Suehiro E, Shirao S, Suzuki M Neuroprotective effects of ebselen following forebrain3ischemia: involvement of glutamate and nitric oxide. Neurol Med Chir (Tokyo).2011;51:337-343.
Block ML, Hong JS Microglia and inflammation-mediated neurodegeneration: multiple triggers with a commonmechanism. Prog Neurobiol.2005;76:77-98.
4Straiko MM, Gudelsky GA, Coolen LM, Harrison R, Zemlan FP Treatment with trimethyltin promotes the formationof cleaved tau in the rat brain. J Neurosci Res.2006;84:1116-1123.
5Farias G, Cornejo A, Jimenez J, Guzman L, Maccioni RB Mechanisms of tau self-aggregation and neurotoxicity. CurrAlzheimer Res.2011;8:608-614.
6Hanger DP, Anderton BH, Noble W Tau phosphorylation: the therapeutic challenge for neurodegenerative disease.Trends Mol Med.2009;15:112-119.
Liu F, Li B, Tung EJ, Grundke-Iqbal I, Iqbal K, et al. Site-specific effects of tau phosphorylation on its microtubuleassembly activity and self-aggregation. Eur J Neurosci.2007;26:3429-3436.
1Mondragon-Rodriguez S, Mena R, Binder LI, Smith MA, Perry G, et al. Conformational changes and cleavage of tauin Pick bodies parallel the early processing of tau found in Alzheimer pathology. Neuropathol Appl Neurobiol.2008;34:62-75.
2Mondragon-Rodriguez S, Trillaud-Doppia E, Dudilot A, Bourgeois C, Lauzon M, et al. Interaction of endogenous tauprotein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation. J Biol Chem.2012;287:32040-32053.
Ho YS, Yang X, Lau JC, Hung CH, Wuwongse S, et al. Endoplasmic reticulum stress induces tau pathology andforms a vicious cycle: implication in Alzheimer's disease pathogenesis. J Alzheimers Dis.2012;28:839-854.
4Kim SU, de Vellis J Stem cell-based cell therapy in neurological diseases: a review. J Neurosci Res.2009;87:2183-2200.
5Woodruff ML, Baisden RH, Nonneman AJ Anatomical and behavioral sequelae of fetal brain transplants in rats withtrimethyltin-induced neurodegeneration. Neurotoxicology.1991;12:427-444.
6Roy A, Agrawal AK, Husain R, Dubey MP, Seth PK Cholinergic and serotonergic alterations in the rat hippocampusfollowing trimethyltin exposure and fetal neural transplantation. Neurosci Lett.1999;259:173-176.
Yoneyama M, Seko K, Kawada K, Sugiyama C, Ogita K High susceptibility of cortical neural progenitor cells totrimethyltin toxicity: involvement of both caspases and calpain in cell death. Neurochem Int.2009;55:257-264.
1Martino G, Pluchino S, Bonfanti L, Schwartz M Brain regeneration in physiology and pathology: the immunesignature driving therapeutic plasticity of neural stem cells. Physiol Rev.2011;91:1281-1304.
2Parent JM Injury-induced neurogenesis in the adult mammalian brain. Neuroscientist.2003;9:261-272.
Corvino V, Geloso MC, Cavallo V, Guadagni E, Passalacqua R, et al. Enhanced neurogenesis duringtrimethyltin-induced neurodegeneration in the hippocampus of the adult rat. Brain Res Bull.2005;65:471-477.
4McPherson CA, Aoyama M, Harry GJ Interleukin (IL)-1and IL-6regulation of neural progenitor cell proliferationwith hippocampal injury: differential regulatory pathways in the subgranular zone (SGZ) of the adolescent and maturemouse brain. Brain Behav Immun.2011;25:850-862.
5Gray WP Neuropeptide Y signalling on hippocampal stem cells in health and disease. Mol Cell Endocrinol.2008;288:52-62.
6Corvino V, Marchese E, Giannetti S, Lattanzi W, Bonvissuto D, et al. The neuroprotective and neurogenic effects ofneuropeptide Y administration in an animal model of hippocampal neurodegeneration and temporal lobe epilepsy inducedby trimethyltin. J Neurochem.2012;122:415-426.
[1] Geloso MC, Corvino V, Michetti F Trimethyltin-induced hippocampal degenerationas a tool to investigate neurodegenerative processes. Neurochem Int.2011;58:729-738.
[2] Chang LW, Wenger GR, McMillan DE, Dyer RS Species and strain comparison ofacute neurotoxic effects of trimethyltin in mice and rats. Neurobehav Toxicol Teratol.1983;5:337-350.
[3] Harry GJ, Lefebvre d'Hellencourt C Dentate gyrus: alterations that occur withhippocampal injury. Neurotoxicology.2003;24:343-356.
[4] Balaban CD, O'Callaghan JP, Billingsley ML Trimethyltin-induced neuronal damagein the rat brain: comparative studies using silver degeneration stains,immunocytochemistry and immunoassay for neuronotypic and gliotypic proteins.Neuroscience.1988;26:337-361.
[5] Andersson H, Wetmore C, Lindqvist E, Luthman J, Olson L Trimethyltin exposure inthe rat induces delayed changes in brain-derived neurotrophic factor, fos and heatshock protein70. Neurotoxicology.1997;18:147-159.
[6] Casalbore P, Barone I, Felsani A, D'Agnano I, Michetti F, et al. Neural stem cellsmodified to express BDNF antagonize trimethyltin-induced neurotoxicity throughPI3K/Akt and MAP kinase pathways. J Cell Physiol.2010;224:710-721.
[7] Greenberg ME, Xu B, Lu B, Hempstead BL New insights in the biology of BDNFsynthesis and release: implications in CNS function. J Neurosci.2009;29:12764-12767.
[8] Kang H, Schuman EM A requirement for local protein synthesis inneurotrophin-induced hippocampal synaptic plasticity. Science.1996;273:1402-1406.
[9] Gonzalez-Billault C, Engelke M, Jimenez-Mateos EM, Wandosell F, Caceres A, et al.Participation of structural microtubule-associated proteins (MAPs) in the developmentof neuronal polarity. J Neurosci Res.2002;67:713-719.
[10] Avila J, Lucas JJ, Perez M, Hernandez F Role of tau protein in both physiologicaland pathological conditions. Physiol Rev.2004;84:361-384.
[11] Hernandez F, Lucas JJ, Cuadros R, Avila J GSK-3dependent phosphoepitopesrecognized by PHF-1and AT-8antibodies are present in different tau isoforms.Neurobiol Aging.2003;24:1087-1094.
[12] Hoogenraad CC, Bradke F Control of neuronal polarity and plasticity--a renaissancefor microtubules? Trends Cell Biol.2009;19:669-676.
[13] Peng S, Wuu J, Mufson EJ, Fahnestock M Precursor form of brain-derivedneurotrophic factor and mature brain-derived neurotrophic factor are decreased in thepre-clinical stages of Alzheimer's disease. J Neurochem.2005;93:1412-1421.
[14] Fulga TA, Elson-Schwab I, Khurana V, Steinhilb ML, Spires TL, et al. Abnormalbundling and accumulation of F-actin mediates tau-induced neuronal degeneration invivo. Nat Cell Biol.2007;9:139-148.
[15] Brunden KR, Trojanowski JQ, Lee VM Advances in tau-focused drug discovery forAlzheimer's disease and related tauopathies. Nat Rev Drug Discov.2009;8:783-793.
[16] Wang JZ, Liu F Microtubule-associated protein tau in development, degeneration andprotection of neurons. Prog Neurobiol.2008;85:148-175.
[17] Spires-Jones TL, Stoothoff WH, de Calignon A, Jones PB, Hyman BT Taupathophysiology in neurodegeneration: a tangled issue. Trends Neurosci.2009;32:150-159.
[18] Vega IE, Hamano T, Propost JA, Grenningloh G, Yen SH Taxol and tauoverexpression induced calpain-dependent degradation of the microtubule-destabilizing protein SCG10. Exp Neurol.2006;202:152-160.
[19] Niewiadomska G, Baksalerska-Pazera M, Riedel G Altered cellular distribution ofphospho-tau proteins coincides with impaired retrograde axonal transport in neurons ofaged rats. Ann N Y Acad Sci.2005;1048:287-295.
[20] Zhang B, Maiti A, Shively S, Lakhani F, McDonald-Jones G, et al.Microtubule-binding drugs offset tau sequestration by stabilizing microtubules andreversing fast axonal transport deficits in a tauopathy model. Proc Natl Acad Sci U S A.2005;102:227-231.
[21] Rapoport M, Dawson HN, Binder LI, Vitek MP, Ferreira A Tau is essential to beta-amyloid-induced neurotoxicity. Proc Natl Acad Sci U S A.2002;99:6364-6369.
[22] Morris M, Maeda S, Vossel K, Mucke L The many faces of tau. Neuron.2011;70:410-426.
[23] Wolfe MS Tau mutations in neurodegenerative diseases. J Biol Chem.2009;284:6021-6025.
[24] Papanikolopoulou K, Kosmidis S, Grammenoudi S, Skoulakis EM Phosphorylationdifferentiates tau-dependent neuronal toxicity and dysfunction. Biochem Soc Trans.2010;38:981-987.
[25] Liu L, Drouet V, Wu JW, Witter MP, Small SA, et al. Trans-synaptic spread of taupathology in vivo. PLoS One.2012;7: e31302.
[26] Nagahara AH, Tuszynski MH Potential therapeutic uses of BDNF in neurologicaland psychiatric disorders. Nat Rev Drug Discov.2011;10:209-219.
[27] Figiel I, Fiedorowicz A Trimethyltin-evoked neuronal apoptosis and glia response inmixed cultures of rat hippocampal dentate gyrus: a new model for the study of the celltype-specific influence of neurotoxins. Neurotoxicology.2002;23:77-86.
[28] Aksamitiene E, Kiyatkin A, Kholodenko BN Cross-talk between mitogenicRas/MAPK and survival PI3K/Akt pathways: a fine balance. Biochem Soc Trans.2012;40:139-146.
[29] Qing Y, Liang Y, Du Q, Fan P, Xu H, et al. Apoptosis induced by trimethyltinchloride in human neuroblastoma cells SY5Y is regulated by a balance and cross-talkbetween NF-kappaB and MAPKs signaling pathways. Arch Toxicol.87:1273-1285.
[30] Tran HY, Shin EJ, Saito K, Nguyen XK, Chung YH, et al. Protective potential ofIL-6against trimethyltin-induced neurotoxicity in vivo. Free Radic Biol Med.52:1159-1174.
[31] Dopp E, Hartmann LM, von Recklinghausen U, Florea AM, Rabieh S, et al. Thecyto-and genotoxicity of organotin compounds is dependent on the cellular uptakecapability. Toxicology.2007;232:226-234.
[32] Piacentini R, Gangitano C, Ceccariglia S, Del Fa A, Azzena GB, et al. Dysregulationof intracellular calcium homeostasis is responsible for neuronal death in anexperimental model of selective hippocampal degeneration induced by trimethyltin. JNeurochem.2008;105:2109-2121.
[33] Zhang L, Li L, Prabhakaran K, Borowitz JL, Isom GE Trimethyltin-inducedapoptosis is associated with upregulation of inducible nitric oxide synthase and Bax ina hippocampal cell line. Toxicol Appl Pharmacol.2006;216:34-43.
[34] Duchen MR Mitochondria, calcium-dependent neuronal death and neurodegenerativedisease. Pflugers Arch.464:111-121.
[35] Cai J, Wang M, Li B, Wang C, Chen Y, et al. Apoptotic and necrotic actionmechanisms of trimethyltin in human hepatoma G2(HepG2) cells. Chem Res Toxicol.2009;22:1582-1587.
[36] Geloso MC, Vercelli A, Corvino V, Repici M, Boca M, et al. Cyclooxygenase-2andcaspase3expression in trimethyltin-induced apoptosis in the mouse hippocampus. ExpNeurol.2002;175:152-160.
[37] Minghetti L Role of inflammation in neurodegenerative diseases. Curr Opin Neurol.2005;18:315-321.
[38] Lu B, Nagappan G, Guan X, Nathan PJ, Wren P BDNF-based synaptic repair as adisease-modifying strategy for neurodegenerative diseases. Nat Rev Neurosci.2013;14:401-416.
[39] Koda T, Kuroda Y, Imai H Protective effect of rutin against spatial memoryimpairment induced by trimethyltin in rats. Nutr Res.2008;28:629-634.
[40] Koda T, Kuroda Y, Imai H Rutin supplementation in the diet has protective effectsagainst toxicant-induced hippocampal injury by suppression of microglial activationand pro-inflammatory cytokines: protective effect of rutin against toxicant-inducedhippocampal injury. Cell Mol Neurobiol.2009;29:523-531.
[41] Kim JK, Bae H, Kim MJ, Choi SJ, Cho HY, et al. Inhibitory effect of Poncirustrifoliate on acetylcholinesterase and attenuating activity against trimethyltin-inducedlearning and memory impairment. Biosci Biotechnol Biochem.2009;73:1105-1112.
[42] Czlonkowska A, Kurkowska-Jastrzebska I Inflammation and gliosis in neurologicaldiseases--clinical implications. J Neuroimmunol.2011;231:78-85.
[43] Funk JA, Gohlke J, Kraft AD, McPherson CA, Collins JB, et al. Voluntary exerciseprotects hippocampal neurons from trimethyltin injury: possible role of interleukin-6tomodulate tumor necrosis factor receptor-mediated neurotoxicity. Brain Behav Immun.2011;25:1063-1077.
[44] Shuto M, Higuchi K, Sugiyama C, Yoneyama M, Kuramoto N, et al. Endogenous andexogenous glucocorticoids prevent trimethyltin from causing neuronal degeneration ofthe mouse brain in vivo: involvement of oxidative stress pathways. J Pharmacol Sci.2009;110:424-436.
[45] Shin EJ, Suh SK, Lim YK, Jhoo WK, Hjelle OP, et al. Ascorbate attenuatestrimethyltin-induced oxidative burden and neuronal degeneration in the rathippocampus by maintaining glutathione homeostasis. Neuroscience.2005;133:715-727.
[46] Arancio O, Chao MV Neurotrophins, synaptic plasticity and dementia. Curr OpinNeurobiol.2007;17:325-330.
[47] Bhatt DH, Zhang S, Gan WB Dendritic spine dynamics. Annu Rev Physiol.2009;71:261-282.
[48] Hemmings BA Akt signaling: linking membrane events to life and death decisions.Science.1997;275:628-630.
[49] Impey S, Obrietan K, Storm DR Making new connections: role of ERK/MAP kinasesignaling in neuronal plasticity. Neuron.1999;23:11-14.
[50] Dent P Crosstalk between ERK, AKT, and cell survival. Cancer Biol Ther.2014;15:245-246.
[51] Caceres A, Kosik KS Inhibition of neurite polarity by tau antisense oligonucleotidesin primary cerebellar neurons. Nature.1990;343:461-463.
[52] Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW A protein factor essentialfor microtubule assembly. Proc Natl Acad Sci U S A.1975;72:1858-1862.
[53] Thies E, Mandelkow EM Missorting of tau in neurons causes degeneration ofsynapses that can be rescued by the kinase MARK2/Par-1. J Neurosci.2007;27:2896-2907.
[54] Dickstein DL, Brautigam H, Stockton SD, Jr., Schmeidler J, Hof PR Changes indendritic complexity and spine morphology in transgenic mice expressing humanwild-type tau. Brain Struct Funct.2010;214:161-179.
[55] Eckermann K, Mocanu MM, Khlistunova I, Biernat J, Nissen A, et al. Thebeta-propensity of Tau determines aggregation and synaptic loss in inducible mousemodels of tauopathy. J Biol Chem.2007;282:31755-31765.
[56] Jaworski J, Kapitein LC, Gouveia SM, Dortland BR, Wulf PS, et al. Dynamicmicrotubules regulate dendritic spine morphology and synaptic plasticity. Neuron.2009;61:85-100.
[57] Erturk A, Hellal F, Enes J, Bradke F Disorganized microtubules underlie theformation of retraction bulbs and the failure of axonal regeneration. J Neurosci.2007;27:9169-9180.
[58] Yuan J, Yankner BA Apoptosis in the nervous system. Nature.2000;407:802-809.
[59] Drewes G, Trinczek B, Illenberger S, Biernat J, Schmitt-Ulms G, et al.Microtubule-associated protein/microtubule affinity-regulating kinase (p110mark). Anovel protein kinase that regulates tau-microtubule interactions and dynamic instabilityby phosphorylation at the Alzheimer-specific site serine262. J Biol Chem.1995;270:7679-7688.
[60] Utton MA, Vandecandelaere A, Wagner U, Reynolds CH, Gibb GM, et al.Phosphorylation of tau by glycogen synthase kinase3beta affects the ability of tau topromote microtubule self-assembly. Biochem J.1997;323(Pt3):741-747.
[61] Biernat J, Gustke N, Drewes G, Mandelkow EM, Mandelkow E Phosphorylation ofSer262strongly reduces binding of tau to microtubules: distinction between PHF-likeimmunoreactivity and microtubule binding. Neuron.1993;11:153-163.
[62] Polydoro M, Acker CM, Duff K, Castillo PE, Davies P Age-dependent impairment ofcognitive and synaptic function in the htau mouse model of tau pathology. J Neurosci.2009;29:10741-10749.
[63] Johnson GV, Stoothoff WH Tau phosphorylation in neuronal cell function anddysfunction. J Cell Sci.2004;117:5721-5729.
[64] Liu F, Li B, Tung EJ, Grundke-Iqbal I, Iqbal K, et al. Site-specific effects of tauphosphorylation on its microtubule assembly activity and self-aggregation. Eur JNeurosci.2007;26:3429-3436.
[65] Mondragon-Rodriguez S, Mena R, Binder LI, Smith MA, Perry G, et al.Conformational changes and cleavage of tau in Pick bodies parallel the earlyprocessing of tau found in Alzheimer pathology. Neuropathol Appl Neurobiol.2008;34:62-75.
[66] Mondragon-Rodriguez S, Trillaud-Doppia E, Dudilot A, Bourgeois C, Lauzon M, et al.Interaction of endogenous tau protein with synaptic proteins is regulated byN-methyl-D-aspartate receptor-dependent tau phosphorylation. J Biol Chem.2012;287:32040-32053.
[67] Ho YS, Yang X, Lau JC, Hung CH, Wuwongse S, et al. Endoplasmic reticulum stressinduces tau pathology and forms a vicious cycle: implication in Alzheimer's diseasepathogenesis. J Alzheimers Dis.2012;28:839-854.
[68] Kosik KS, Kowall NW, McKee A Along the way to a neurofibrillary tangle: a look atthe structure of tau. Ann Med.1989;21:109-112.
[69] Lu B BDNF and activity-dependent synaptic modulation. Learn Mem.2003;10:86-98.
[70] Haque N, Tanaka T, Iqbal K, Grundke-Iqbal I Regulation of expression,phosphorylation and biological activity of tau during differentiation in SY5Y cells.Brain Res.1999;838:69-77.
[71] Whiteman IT, Minamide LS, Goh de L, Bamburg JR, Goldsbury C Rapid changes inphospho-MAP/tau epitopes during neuronal stress: cofilin-actin rods primarily recruitmicrotubule binding domain epitopes. PLoS One.2011;6: e20878.
[72] Park H, Poo MM Neurotrophin regulation of neural circuit development and function.Nat Rev Neurosci.2013;14:7-23.
[73] Cohen-Cory S, Fraser SE Effects of brain-derived neurotrophic factor on optic axonbranching and remodelling in vivo. Nature.1995;378:192-196.
[74] Ji Y, Lu Y, Yang F, Shen W, Tang TT, et al. Acute and gradual increases in BDNFconcentration elicit distinct signaling and functions in neurons. Nat Neurosci.2010;13:302-309.
[75] Tyler WJ, Pozzo-Miller L Miniature synaptic transmission and BDNF modulatedendritic spine growth and form in rat CA1neurones. J Physiol.2003;553:497-509.
[76] Horch HW, Kruttgen A, Portbury SD, Katz LC Destabilization of cortical dendritesand spines by BDNF. Neuron.1999;23:353-364.
[77] Brandt R, Leger J, Lee G Interaction of tau with the neural plasma membranemediated by tau's amino-terminal projection domain. J Cell Biol.1995;131:1327-1340.
[78] Vasquez RJ, Howell B, Yvon AM, Wadsworth P, Cassimeris L Nanomolarconcentrations of nocodazole alter microtubule dynamic instability in vivo and in vitro.Mol Biol Cell.1997;8:973-985.
[79] Zempel H, Thies E, Mandelkow E, Mandelkow EM Abeta oligomers cause localizedCa(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation,and destruction of microtubules and spines. J Neurosci.2010;30:11938-11950.
[80] Ballatore C, Lee VM, Trojanowski JQ Tau-mediated neurodegeneration inAlzheimer's disease and related disorders. Nat Rev Neurosci.2007;8:663-672.
[81] Drubin D, Kobayashi S, Kellogg D, Kirschner M Regulation of microtubule proteinlevels during cellular morphogenesis in nerve growth factor-treated PC12cells. J CellBiol.1988;106:1583-1591.
[82] David DC, Layfield R, Serpell L, Narain Y, Goedert M, et al. Proteasomaldegradation of tau protein. J Neurochem.2002;83:176-185.
[83] Jinwal UK, Trotter JH, Abisambra JF, Koren J,3rd, Lawson LY, et al. The Hsp90kinase co-chaperone Cdc37regulates tau stability and phosphorylation dynamics. JBiol Chem.2011;286:16976-16983.
[84] Yoshizaki C, Tsukane M, Yamauchi T Overexpression of tau leads to the stimulationof neurite outgrowth, the activation of caspase3activity, and accumulation andphosphorylation of tau in neuroblastoma cells on cAMP treatment. Neurosci Res.2004;49:363-371.
[85] Sultan A, Nesslany F, Violet M, Begard S, Loyens A, et al. Nuclear tau, a key playerin neuronal DNA protection. J Biol Chem.2011;286:4566-4575.
[86] Strittmatter WJ, Saunders AM, Goedert M, Weisgraber KH, Dong LM, et al.Isoform-specific interactions of apolipoprotein E with microtubule-associated proteintau: implications for Alzheimer disease. Proc Natl Acad Sci U S A.1994;91:11183-11186.
[87] Bhaskar K, Yen SH, Lee G Disease-related modifications in tau affect the interactionbetween Fyn and Tau. J Biol Chem.2005;280:35119-35125.
[88] Dawson HN, Cantillana V, Jansen M, Wang H, Vitek MP, et al. Loss of tau elicitsaxonal degeneration in a mouse model of Alzheimer's disease. Neuroscience.2010;169:516-531.
[89] Jin M, Shepardson N, Yang T, Chen G, Walsh D, et al. Soluble amyloid beta-proteindimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation andneuritic degeneration. Proc Natl Acad Sci U S A.2011;108:5819-5824.
[90] Planel E, Tatebayashi Y, Miyasaka T, Liu L, Wang L, et al. Insulin dysfunctioninduces in vivo tau hyperphosphorylation through distinct mechanisms. J Neurosci.2007;27:13635-13648.
[91] Miao Y, Chen J, Zhang Q, Sun A Deletion of tau attenuates heat shock-induced injuryin cultured cortical neurons. J Neurosci Res.2010;88:102-110.
[92] Noble W, Pooler AM, Hanger DP Advances in tau-based drug discovery. Expert OpinDrug Discov.2011;6:797-810.
[93] Gordon D, Kidd GJ, Smith R Antisense suppression of tau in cultured ratoligodendrocytes inhibits process formation. J Neurosci Res.2008;86:2591-2601.
[94] Caccamo A, Maldonado MA, Bokov AF, Majumder S, Oddo S CBP gene transferincreases BDNF levels and ameliorates learning and memory deficits in a mousemodel of Alzheimer's disease. Proc Natl Acad Sci U S A.2010;107:22687-22692.
[95] Blurton-Jones M, Kitazawa M, Martinez-Coria H, Castello NA, Muller FJ, et al.Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimerdisease. Proc Natl Acad Sci U S A.2009;106:13594-13599.
[96] Encinas M, Iglesias M, Liu Y, Wang H, Muhaisen A, et al. Sequential treatment ofSH-SY5Y cells with retinoic acid and brain-derived neurotrophic factor gives rise tofully differentiated, neurotrophic factor-dependent, human neuron-like cells. JNeurochem.2000;75:991-1003.
[97] Jamsa A, Hasslund K, Cowburn RF, Backstrom A, Vasange M The retinoic acid andbrain-derived neurotrophic factor differentiated SH-SY5Y cell line as a model forAlzheimer's disease-like tau phosphorylation. Biochem Biophys Res Commun.2004;319:993-1000.
[1] Besser R, Kramer G, Thumler R, Bohl J, Gutmann L, et al. Acute trimethyltinlimbic-cerebellar syndrome. Neurology.1987;37:945-950.
[2] Balaban CD, O'Callaghan JP, Billingsley ML Trimethyltin-induced neuronaldamage in the rat brain: comparative studies using silver degeneration stains,immunocytochemistry and immunoassay for neuronotypic and gliotypic proteins.Neuroscience.1988;26:337-361.
[3] Chang LW, Dyer RS A time-course study of trimethyltin induced neuropathology inrats. Neurobehav Toxicol Teratol.1983;5:443-459.
[4] Ishikawa K, Kubo T, Shibanoki S, Matsumoto A, Hata H, et al. Hippocampaldegeneration inducing impairment of learning in rats: model of dementia? BehavBrain Res.1997;83:39-44.
[5] Ishikura N, Tsunashima K, Watanabe K, Nishimura T, Minabe Y, et al. NeuropeptideY and somatostatin participate differently in the seizure-generating mechanismsfollowing trimethyltin-induced hippocampal damage. Neurosci Res.2002;44:237-248.
[6] Nilsberth C, Kostyszyn B, Luthman J Changes in APP, PS1and other factors relatedto Alzheimer's disease pathophysiology after trimethyltin-induced brain lesion in therat. Neurotox Res.2002;4:625-636.
[7] Boyer IJ Toxicity of dibutyltin, tributyltin and other organotin compounds tohumans and to experimental animals. Toxicology.1989;55:253-298.
[8] Borghi V, Porte C Organotin pollution in deep-sea fish from the northwesternMediterranean. Environ Sci Technol.2002;36:4224-4228.
[9] Chang LW The neurotoxicology and pathology of organomercury, organolead, andorganotin. J Toxicol Sci.1990;15Suppl4:125-151.
[10] Yoo CI, Kim Y, Jeong KS, Sim CS, Choy N, et al. A case of acute organotinpoisoning. J Occup Health.2007;49:305-310.
[11] Holloway LN, Pannell KH, Whalen MM Effects of a series of triorganotins on ATPlevels in human natural killer cells. Environ Toxicol Pharmacol.2008;25:43-50.
[12] Fortemps E, Amand G, Bomboir A, Lauwerys R, Laterre EC Trimethyltin poisoning.Report of two cases. Int Arch Occup Environ Health.1978;41:1-6.
[13] Ross WD, Emmett EA, Steiner J, Tureen R Neurotoxic effects of occupationalexposure to organotins. Am J Psychiatry.1981;138:1092-1095.
[14] Kreyberg S, Torvik A, Bjorneboe A, Wiik-Larsen W, Jacobsen D Trimethyltinpoisoning: report of a case with postmortem examination. Clin Neuropathol.1992;11:256-259.
[15] Ghosh BB, Talukder G, Sharma A Frequency of chromosome aberrations induced bytrimethyltin chloride in human peripheral blood lymphocytes in vitro: related to ageof donors. Mech Ageing Dev.1991;57:125-137.
[16] Gomez FD, Apodaca P, Holloway LN, Pannell KH, Whalen MM Effect of a seriesof triorganotins on the immune function of human natural killer cells. Environ ToxicolPharmacol.2007;23:18-24.
[17] Ohno H, Suzuki M, Nakashima S, Aoyama T, Mitani K [Determination of organotincompounds in plastic products by GC/MS after ethyl derivatization with sodiumtetraethylborate]. Shokuhin Eiseigaku Zasshi.2002;43:208-214.
[18] Fent K Ecotoxicology of organotin compounds. Crit Rev Toxicol.1996;26:1-117.
[19] Teuten EL, Saquing JM, Knappe DR, Barlaz MA, Jonsson S, et al. Transport andrelease of chemicals from plastics to the environment and to wildlife. Philos Trans RSoc Lond B Biol Sci.2009;364:2027-2045.
[20] Vajda FJ Neuroprotection and neurodegenerative disease. J Clin Neurosci.2002;9:4-8.
[21] Mattson MP Glutamate and neurotrophic factors in neuronal plasticity and disease.Ann N Y Acad Sci.2008;1144:97-112.
[22] Minghetti L Role of inflammation in neurodegenerative diseases. Curr Opin Neurol.2005;18:315-321.
[23] Parent JM Injury-induced neurogenesis in the adult mammalian brain.Neuroscientist.2003;9:261-272.
[24] Geloso MC, Corvino V, Michetti F Trimethyltin-induced hippocampal degenerationas a tool to investigate neurodegenerative processes. Neurochem Int.2011;58:729-738.
[25] Chang LW, Wenger GR, McMillan DE, Dyer RS Species and strain comparison ofacute neurotoxic effects of trimethyltin in mice and rats. Neurobehav Toxicol Teratol.1983;5:337-350.
[26] Harry GJ, Lefebvre d'Hellencourt C Dentate gyrus: alterations that occur withhippocampal injury. Neurotoxicology.2003;24:343-356.
[27] Misiti F, Orsini F, Clementi ME, Lattanzi W, Giardina B, et al. Mitochondrialoxygen consumption inhibition importance for TMT-dependent cell death inundifferentiated PC12cells. Neurochem Int.2008;52:1092-1099.
[28] Billingsley ML, Yun J, Reese BE, Davidson CE, Buck-Koehntop BA, et al.Functional and structural properties of stannin: roles in cellular growth, selectivetoxicity, and mitochondrial responses to injury. J Cell Biochem.2006;98:243-250.
[29] Piacentini R, Gangitano C, Ceccariglia S, Del Fa A, Azzena GB, et al.Dysregulation of intracellular calcium homeostasis is responsible for neuronal deathin an experimental model of selective hippocampal degeneration induced bytrimethyltin. J Neurochem.2008;105:2109-2121.
[30] Ceccariglia S, D'Altocolle A, Del Fa A, Pizzolante F, Caccia E, et al. Cathepsin Dplays a crucial role in the trimethyltin-induced hippocampal neurodegenerationprocess. Neuroscience.174:160-170.
[31] Casalbore P, Barone I, Felsani A, D'Agnano I, Michetti F, et al. Neural stem cellsmodified to express BDNF antagonize trimethyltin-induced neurotoxicity throughPI3K/Akt and MAP kinase pathways. J Cell Physiol.2010;224:710-721.
[32] Andersson H, Wetmore C, Lindqvist E, Luthman J, Olson L Trimethyltin exposurein the rat induces delayed changes in brain-derived neurotrophic factor, fos and heatshock protein70. Neurotoxicology.1997;18:147-159.
[33] Cohen-Cory S, Fraser SE Effects of brain-derived neurotrophic factor on optic axonbranching and remodelling in vivo. Nature.1995;378:192-196.
[34] McAllister AK, Lo DC, Katz LC Neurotrophins regulate dendritic growth indeveloping visual cortex. Neuron.1995;15:791-803.
[35] Ji Y, Lu Y, Yang F, Shen W, Tang TT, et al. Acute and gradual increases in BDNFconcentration elicit distinct signaling and functions in neurons. Nat Neurosci.2010;13:302-309.
[36] Tartaglia N, Du J, Tyler WJ, Neale E, Pozzo-Miller L, et al. Proteinsynthesis-dependent and-independent regulation of hippocampal synapses bybrain-derived neurotrophic factor. J Biol Chem.2001;276:37585-37593.
[37] Horch HW, Kruttgen A, Portbury SD, Katz LC Destabilization of cortical dendritesand spines by BDNF. Neuron.1999;23:353-364.
[38] Pozzo-Miller LD, Gottschalk W, Zhang L, McDermott K, Du J, et al. Impairmentsin high-frequency transmission, synaptic vesicle docking, and synaptic proteindistribution in the hippocampus of BDNF knockout mice. J Neurosci.1999;19:4972-4983.
[39] Otal R, Martinez A, Soriano E Lack of TrkB and TrkC signaling alters thesynaptogenesis and maturation of mossy fiber terminals in the hippocampus. CellTissue Res.2005;319:349-358.
[40] Aguado F, Carmona MA, Pozas E, Aguilo A, Martinez-Guijarro FJ, et al. BDNFregulates spontaneous correlated activity at early developmental stages by increasingsynaptogenesis and expression of the K+/Cl-co-transporter KCC2. Development.2003;130:1267-1280.
[41] Singh B, Henneberger C, Betances D, Arevalo MA, Rodriguez-Tebar A, et al.Altered balance of glutamatergic/GABAergic synaptic input and associated changesin dendrite morphology after BDNF expression in BDNF-deficient hippocampalneurons. J Neurosci.2006;26:7189-7200.
[42] Tanaka J, Horiike Y, Matsuzaki M, Miyazaki T, Ellis-Davies GC, et al. Proteinsynthesis and neurotrophin-dependent structural plasticity of single dendritic spines.Science.2008;319:1683-1687.
[43] Ma YL, Wang HL, Wu HC, Wei CL, Lee EH Brain-derived neurotrophic factorantisense oligonucleotide impairs memory retention and inhibits long-termpotentiation in rats. Neuroscience.1998;82:957-967.
[44] Alonso M, Vianna MR, Izquierdo I, Medina JH Signaling mechanisms mediatingBDNF modulation of memory formation in vivo in the hippocampus. Cell MolNeurobiol.2002;22:663-674.
[45] Nagahara AH, Tuszynski MH Potential therapeutic uses of BDNF in neurologicaland psychiatric disorders. Nat Rev Drug Discov.2011;10:209-219.
[46] Kemppainen S, Rantamaki T, Jeronimo-Santos A, Lavasseur G, Autio H, et al.Impaired TrkB receptor signaling contributes to memory impairment in APP/PS1mice. Neurobiol Aging.2012;33:1122e1123-1139.
[47] Nagahara AH, Merrill DA, Coppola G, Tsukada S, Schroeder BE, et al.Neuroprotective effects of brain-derived neurotrophic factor in rodent and primatemodels of Alzheimer's disease. Nat Med.2009;15:331-337.
[48] Kraft AD, McPherson CA, Harry GJ Heterogeneity of microglia and TNF signalingas determinants for neuronal death or survival. Neurotoxicology.2009;30:785-793.
[49] Tran HY, Shin EJ, Saito K, Nguyen XK, Chung YH, et al. Protective potential ofIL-6against trimethyltin-induced neurotoxicity in vivo. Free Radic Biol Med.2012;52:1159-1174.
[50] Jean Harry G, Bruccoleri A, Lefebvre d'Hellencourt C Differential modulation ofhippocampal chemical-induced injury response by ebselen, pentoxifylline, andTNFalpha-, IL-1alpha-, and IL-6-neutralizing antibodies. J Neurosci Res.2003;73:526-536.
[51] Brabeck C, Michetti F, Geloso MC, Corvino V, Goezalan F, et al. Expression ofEMAP-II by activated monocytes/microglial cells in different regions of the rathippocampus after trimethyltin-induced brain damage. Exp Neurol.2002;177:341-346.
[52] Little AR, Miller DB, Li S, Kashon ML, O'Callaghan JP Trimethyltin-inducedneurotoxicity: gene expression pathway analysis, q-RT-PCR and immunoblottingreveal early effects associated with hippocampal damage and gliosis. NeurotoxicolTeratol.2012;34:72-82.
[53] Liu Y, Imai H, Sadamatsu M, Tsunashima K, Kato N Cytokines participate inneuronal death induced by trimethyltin in the rat hippocampus via type IIglucocorticoid receptors. Neurosci Res.2005;51:319-327.
[54] Corvino V, Marchese E, Zarkovic N, Zarkovic K, Cindric M, et al. Distribution andtime-course of4-hydroxynonenal, heat shock protein110/105family members andcyclooxygenase-2expression in the hippocampus of rat during trimethyltin-inducedneurodegeneration. Neurochem Res.2011;36:1490-1500.
[55] Allaman I, Belanger M, Magistretti PJ Astrocyte-neuron metabolic relationships:for better and for worse. Trends Neurosci.2011;34:76-87.
[56] Zarkovic N, Zarkovic K, Schaur RJ, Stolc S, Schlag G, et al.4-Hydroxynonenal as asecond messenger of free radicals and growth modifying factor. Life Sci.1999;65:1901-1904.
[57] Coyle JT, Puttfarcken P Oxidative stress, glutamate, and neurodegenerativedisorders. Science.1993;262:689-695.
[58] Schulz JB, Lindenau J, Seyfried J, Dichgans J Glutathione, oxidative stress andneurodegeneration. Eur J Biochem.2000;267:4904-4911.
[59] Ali SF, LeBel CP, Bondy SC Reactive oxygen species formation as a biomarker ofmethylmercury and trimethyltin neurotoxicity. Neurotoxicology.1992;13:637-648.
[60] Shin EJ, Suh SK, Lim YK, Jhoo WK, Hjelle OP, et al. Ascorbate attenuatestrimethyltin-induced oxidative burden and neuronal degeneration in the rathippocampus by maintaining glutathione homeostasis. Neuroscience.2005;133:715-727.
[61] Haddad el B, McCluskie K, Birrell MA, Dabrowski D, Pecoraro M, et al.Differential effects of ebselen on neutrophil recruitment, chemokine, andinflammatory mediator expression in a rat model of lipopolysaccharide-inducedpulmonary inflammation. J Immunol.2002;169:974-982.
[62] Koizumi H, Fujisawa H, Suehiro E, Shirao S, Suzuki M Neuroprotective effects ofebselen following forebrain ischemia: involvement of glutamate and nitric oxide.Neurol Med Chir (Tokyo).2011;51:337-343.
[63] Block ML, Hong JS Microglia and inflammation-mediated neurodegeneration:multiple triggers with a common mechanism. Prog Neurobiol.2005;76:77-98.
[64] Straiko MM, Gudelsky GA, Coolen LM, Harrison R, Zemlan FP Treatment withtrimethyltin promotes the formation of cleaved tau in the rat brain. J Neurosci Res.2006;84:1116-1123.
[65] Farias G, Cornejo A, Jimenez J, Guzman L, Maccioni RB Mechanisms of tauself-aggregation and neurotoxicity. Curr Alzheimer Res.2011;8:608-614.
[66] Hanger DP, Anderton BH, Noble W Tau phosphorylation: the therapeutic challengefor neurodegenerative disease. Trends Mol Med.2009;15:112-119.
[67] Liu F, Li B, Tung EJ, Grundke-Iqbal I, Iqbal K, et al. Site-specific effects of tauphosphorylation on its microtubule assembly activity and self-aggregation. Eur JNeurosci.2007;26:3429-3436.
[68] Mondragon-Rodriguez S, Mena R, Binder LI, Smith MA, Perry G, et al.Conformational changes and cleavage of tau in Pick bodies parallel the earlyprocessing of tau found in Alzheimer pathology. Neuropathol Appl Neurobiol.2008;34:62-75.
[69] Mondragon-Rodriguez S, Trillaud-Doppia E, Dudilot A, Bourgeois C, Lauzon M, et al.Interaction of endogenous tau protein with synaptic proteins is regulated byN-methyl-D-aspartate receptor-dependent tau phosphorylation. J Biol Chem.2012;287:32040-32053.
[70] Ho YS, Yang X, Lau JC, Hung CH, Wuwongse S, et al. Endoplasmic reticulumstress induces tau pathology and forms a vicious cycle: implication in Alzheimer'sdisease pathogenesis. J Alzheimers Dis.2012;28:839-854.
[71] Kim SU, de Vellis J Stem cell-based cell therapy in neurological diseases: a review.J Neurosci Res.2009;87:2183-2200.
[72] Woodruff ML, Baisden RH, Nonneman AJ Anatomical and behavioral sequelae offetal brain transplants in rats with trimethyltin-induced neurodegeneration.Neurotoxicology.1991;12:427-444.
[73] Roy A, Agrawal AK, Husain R, Dubey MP, Seth PK Cholinergic and serotonergicalterations in the rat hippocampus following trimethyltin exposure and fetal neuraltransplantation. Neurosci Lett.1999;259:173-176.
[74] Yoneyama M, Seko K, Kawada K, Sugiyama C, Ogita K High susceptibility ofcortical neural progenitor cells to trimethyltin toxicity: involvement of both caspasesand calpain in cell death. Neurochem Int.2009;55:257-264.
[75] Martino G, Pluchino S, Bonfanti L, Schwartz M Brain regeneration in physiologyand pathology: the immune signature driving therapeutic plasticity of neural stemcells. Physiol Rev.2011;91:1281-1304.
[76] Corvino V, Geloso MC, Cavallo V, Guadagni E, Passalacqua R, et al. Enhancedneurogenesis during trimethyltin-induced neurodegeneration in the hippocampus ofthe adult rat. Brain Res Bull.2005;65:471-477.
[77] McPherson CA, Aoyama M, Harry GJ Interleukin (IL)-1and IL-6regulation ofneural progenitor cell proliferation with hippocampal injury: differential regulatorypathways in the subgranular zone (SGZ) of the adolescent and mature mouse brain.Brain Behav Immun.2011;25:850-862.
[78] Gray WP Neuropeptide Y signalling on hippocampal stem cells in health anddisease. Mol Cell Endocrinol.2008;288:52-62.
[79] Corvino V, Marchese E, Giannetti S, Lattanzi W, Bonvissuto D, et al. Theneuroprotective and neurogenic effects of neuropeptide Y administration in an animalmodel of hippocampal neurodegeneration and temporal lobe epilepsy induced bytrimethyltin. J Neurochem.2012;122:415-426.
2Chang LW, Wenger GR, McMillan DE, Dyer RS Species and strain comparison of acute neurotoxic effects oftrimethyltin in mice and rats. Neurobehav Toxicol Teratol.1983;5:337-350.
3Harry GJ, Lefebvre d'Hellencourt C Dentate gyrus: alterations that occur with hippocampal injury. Neurotoxicology.2003;24:343-356.
4Balaban CD, O'Callaghan JP, Billingsley ML Trimethyltin-induced neuronal damage in the rat brain: comparativestudies using silver degeneration stains, immunocytochemistry and immunoassay for neuronotypic and gliotypic proteins.Neuroscience.1988;26:337-361.
1Andersson H, Wetmore C, Lindqvist E, Luthman J, Olson L Trimethyltin exposure in the rat induces delayed changesin brain-derived neurotrophic factor, fos and heat shock protein70. Neurotoxicology.1997;18:147-159.
2Casalbore P, Barone I, Felsani A, D'Agnano I, Michetti F, et al. Neural stem cells modified to express BDNFantagonize trimethyltin-induced neurotoxicity through PI3K/Akt and MAP kinase pathways. J Cell Physiol.2010;224:710-721.
3Greenberg ME, Xu B, Lu B, Hempstead BL New insights in the biology of BDNF synthesis and release: implicationsin CNS function. J Neurosci.2009;29:12764-12767.
Kang H, Schuman EM A requirement for local protein synthesis in neurotrophin-induced hippocampal synapticplasticity. Science.1996;273:1402-1406.
5Gonzalez-Billault C, Engelke M, Jimenez-Mateos EM, Wandosell F, Caceres A, et al. Participation of structuralmicrotubule-associated proteins (MAPs) in the development of neuronal polarity. J Neurosci Res.2002;67:713-719.
6Avila J, Lucas JJ, Perez M, Hernandez F Role of tau protein in both physiological and pathological conditions.Physiol Rev.2004;84:361-384.
7Hernandez F, Lucas JJ, Cuadros R, Avila J GSK-3dependent phosphoepitopes recognized by PHF-1and AT-8antibodies are present in different tau isoforms. Neurobiol Aging.2003;24:1087-1094.
Hoogenraad CC, Bradke F Control of neuronal polarity and plasticity--a renaissance for microtubules? Trends CellBiol.2009;19:669-676.
1Peng S, Wuu J, Mufson EJ, Fahnestock M Precursor form of brain-derived neurotrophic factor and maturebrain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer's disease. J Neurochem.2005;93:1412-1421.
2Fulga TA, Elson-Schwab I, Khurana V, Steinhilb ML, Spires TL, et al. Abnormal bundling and accumulation ofF-actin mediates tau-induced neuronal degeneration in vivo. Nat Cell Biol.2007;9:139-148.
3Brunden KR, Trojanowski JQ, Lee VM Advances in tau-focused drug discovery for Alzheimer's disease and relatedtauopathies. Nat Rev Drug Discov.2009;8:783-793.
4Wang JZ, Liu F Microtubule-associated protein tau in development, degeneration and protection of neurons. ProgNeurobiol.2008;85:148-175.
5Spires-Jones TL, Stoothoff WH, de Calignon A, Jones PB, Hyman BT Tau pathophysiology in neurodegeneration: atangled issue. Trends Neurosci.2009;32:150-159.
6Vega IE, Hamano T, Propost JA, Grenningloh G, Yen SH Taxol and tau overexpression induced calpain-dependentdegradation of the microtubule-destabilizing protein SCG10. Exp Neurol.2006;202:152-160.
7Niewiadomska G, Baksalerska-Pazera M, Riedel G Altered cellular distribution of phospho-tau proteins coincideswith impaired retrograde axonal transport in neurons of aged rats. Ann N Y Acad Sci.2005;1048:287-295.
8Zhang B, Maiti A, Shively S, Lakhani F, McDonald-Jones G, et al. Microtubule-binding drugs offset tau sequestrationby stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model. Proc Natl Acad Sci U S A.2005;102:227-231.
Rapoport M, Dawson HN, Binder LI, Vitek MP, Ferreira A Tau is essential to beta-amyloid-induced neurotoxicity.Proc Natl Acad Sci U S A.2002;99:6364-6369.
1Morris M, Maeda S, Vossel K, Mucke L The many faces of tau. Neuron.2011;70:410-426.
2Wolfe MS Tau mutations in neurodegenerative diseases. J Biol Chem.2009;284:6021-6025.
3Papanikolopoulou K, Kosmidis S, Grammenoudi S, Skoulakis EM Phosphorylation differentiates tau-dependentneuronal toxicity and dysfunction. Biochem Soc Trans.2010;38:981-987.
4Liu L, Drouet V, Wu JW, Witter MP, Small SA, et al. Trans-synaptic spread of tau pathology in vivo. PLoS One.2012;7: e31302.
Nagahara AH, Tuszynski MH Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat RevDrug Discov.2011;10:209-219.
1Figiel I, Fiedorowicz A Trimethyltin-evoked neuronal apoptosis and glia response in mixed cultures of rathippocampal dentate gyrus: a new model for the study of the cell type-specific influence of neurotoxins. Neurotoxicology.2002;23:77-86.
1Aksamitiene E, Kiyatkin A, Kholodenko BN Cross-talk between mitogenic Ras/MAPK and survival PI3K/Aktpathways: a fine balance. Biochem Soc Trans.2012;40:139-146.
2Qing Y, Liang Y, Du Q, Fan P, Xu H, et al. Apoptosis induced by trimethyltin chloride in human neuroblastoma cellsSY5Y is regulated by a balance and cross-talk between NF-kappaB and MAPKs signaling pathways. Arch Toxicol.87:1273-1285.
3Tran HY, Shin EJ, Saito K, Nguyen XK, Chung YH, et al. Protective potential of IL-6against trimethyltin-inducedneurotoxicity in vivo. Free Radic Biol Med.52:1159-1174.
4Dopp E, Hartmann LM, von Recklinghausen U, Florea AM, Rabieh S, et al. The cyto-and genotoxicity of organotincompounds is dependent on the cellular uptake capability. Toxicology.2007;232:226-234.
5Piacentini R, Gangitano C, Ceccariglia S, Del Fa A, Azzena GB, et al. Dysregulation of intracellular calciumhomeostasis is responsible for neuronal death in an experimental model of selective hippocampal degeneration inducedby trimethyltin. J Neurochem.2008;105:2109-2121.
Zhang L, Li L, Prabhakaran K, Borowitz JL, Isom GE Trimethyltin-induced apoptosis is associated with upregulationof inducible nitric oxide synthase and Bax in a hippocampal cell line. Toxicol Appl Pharmacol.2006;216:34-43.
1Duchen MR Mitochondria, calcium-dependent neuronal death and neurodegenerative disease. Pflugers Arch.464:111-121.
2Zhang L, Li L, Prabhakaran K, Borowitz JL, Isom GE Trimethyltin-induced apoptosis is associated with upregulationof inducible nitric oxide synthase and Bax in a hippocampal cell line. Toxicol Appl Pharmacol.2006;216:34-43.
3Cai J, Wang M, Li B, Wang C, Chen Y, et al. Apoptotic and necrotic action mechanisms of trimethyltin in humanhepatoma G2(HepG2) cells. Chem Res Toxicol.2009;22:1582-1587.
4Geloso MC, Vercelli A, Corvino V, Repici M, Boca M, et al. Cyclooxygenase-2and caspase3expression intrimethyltin-induced apoptosis in the mouse hippocampus. Exp Neurol.2002;175:152-160.
5Minghetti L Role of inflammation in neurodegenerative diseases. Curr Opin Neurol.2005;18:315-321.
Geloso MC, Corvino V, Michetti F Trimethyltin-induced hippocampal degeneration as a tool to investigateneurodegenerative processes. Neurochem Int.2011;58:729-738.
1Lu B, Nagappan G, Guan X, Nathan PJ, Wren P BDNF-based synaptic repair as a disease-modifying strategy forneurodegenerative diseases. Nat Rev Neurosci.2013;14:401-416.
2Casalbore P, Barone I, Felsani A, D'Agnano I, Michetti F, et al. Neural stem cells modified to express BDNFantagonize trimethyltin-induced neurotoxicity through PI3K/Akt and MAP kinase pathways. J Cell Physiol.2010;224:710-721.
Andersson H, Wetmore C, Lindqvist E, Luthman J, Olson L Trimethyltin exposure in the rat induces delayed changesin brain-derived neurotrophic factor, fos and heat shock protein70. Neurotoxicology.1997;18:147-159.
4Koda T, Kuroda Y, Imai H Protective effect of rutin against spatial memory impairment induced by trimethyltin inrats. Nutr Res.2008;28:629-634.
5Koda T, Kuroda Y, Imai H Rutin supplementation in the diet has protective effects against toxicant-inducedhippocampal injury by suppression of microglial activation and pro-inflammatory cytokines: protective effect of rutinagainst toxicant-induced hippocampal injury. Cell Mol Neurobiol.2009;29:523-531.
6Kim JK, Bae H, Kim MJ, Choi SJ, Cho HY, et al. Inhibitory effect of Poncirus trifoliate on acetylcholinesterase andattenuating activity against trimethyltin-induced learning and memory impairment. Biosci Biotechnol Biochem.2009;73:1105-1112.
1Kim JK, Bae H, Kim MJ, Choi SJ, Cho HY, et al. Inhibitory effect of Poncirus trifoliate on acetylcholinesterase andattenuating activity against trimethyltin-induced learning and memory impairment. Biosci Biotechnol Biochem.2009;73:1105-1112.
2Czlonkowska A, Kurkowska-Jastrzebska I Inflammation and gliosis in neurological diseases--clinical implications. JNeuroimmunol.2011;231:78-85.
Funk JA, Gohlke J, Kraft AD, McPherson CA, Collins JB, et al. Voluntary exercise protects hippocampal neuronsfrom trimethyltin injury: possible role of interleukin-6to modulate tumor necrosis factor receptor-mediated neurotoxicity.Brain Behav Immun.2011;25:1063-1077.
4Shuto M, Higuchi K, Sugiyama C, Yoneyama M, Kuramoto N, et al. Endogenous and exogenous glucocorticoidsprevent trimethyltin from causing neuronal degeneration of the mouse brain in vivo: involvement of oxidative stresspathways. J Pharmacol Sci.2009;110:424-436.
5Shin EJ, Suh SK, Lim YK, Jhoo WK, Hjelle OP, et al. Ascorbate attenuates trimethyltin-induced oxidative burdenand neuronal degeneration in the rat hippocampus by maintaining glutathione homeostasis. Neuroscience.2005;133:715-727.
6Arancio O, Chao MV Neurotrophins, synaptic plasticity and dementia. Curr Opin Neurobiol.2007;17:325-330.
1Bhatt DH, Zhang S, Gan WB Dendritic spine dynamics. Annu Rev Physiol.2009;71:261-282.
Polydoro M, Acker CM, Duff K, Castillo PE, Davies P Age-dependent impairment of cognitive and synaptic functionin the htau mouse model of tau pathology. J Neurosci.2009;29:10741-10749.
3Dopp E, Hartmann LM, von Recklinghausen U, Florea AM, Rabieh S, et al. The cyto-and genotoxicity of organotincompounds is dependent on the cellular uptake capability. Toxicology.2007;232:226-234.
4Hemmings BA Akt signaling: linking membrane events to life and death decisions. Science.1997;275:628-630.
5Impey S, Obrietan K, Storm DR Making new connections: role of ERK/MAP kinase signaling in neuronal plasticity.Neuron.1999;23:11-14.
6Aksamitiene E, Kiyatkin A, Kholodenko BN Cross-talk between mitogenic Ras/MAPK and survival PI3K/Aktpathways: a fine balance. Biochem Soc Trans.2012;40:139-146.
7Dent P Crosstalk between ERK, AKT, and cell survival. Cancer Biol Ther.2014;15:245-246.
1Gonzalez-Billault C, Engelke M, Jimenez-Mateos EM, Wandosell F, Caceres A, et al. Participation of structuralmicrotubule-associated proteins (MAPs) in the development of neuronal polarity. J Neurosci Res.2002;67:713-719.
2Caceres A, Kosik KS Inhibition of neurite polarity by tau antisense oligonucleotides in primary cerebellar neurons.Nature.1990;343:461-463.
Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW A protein factor essential for microtubule assembly. ProcNatl Acad Sci U S A.1975;72:1858-1862.
1Thies E, Mandelkow EM Missorting of tau in neurons causes degeneration of synapses that can be rescued by thekinase MARK2/Par-1. J Neurosci.2007;27:2896-2907.
Dickstein DL, Brautigam H, Stockton SD, Jr., Schmeidler J, Hof PR Changes in dendritic complexity and spinemorphology in transgenic mice expressing human wild-type tau. Brain Struct Funct.2010;214:161-179.
3Eckermann K, Mocanu MM, Khlistunova I, Biernat J, Nissen A, et al. The beta-propensity of Tau determinesaggregation and synaptic loss in inducible mouse models of tauopathy. J Biol Chem.2007;282:31755-31765.
4Jaworski J, Kapitein LC, Gouveia SM, Dortland BR, Wulf PS, et al. Dynamic microtubules regulate dendritic spinemorphology and synaptic plasticity. Neuron.2009;61:85-100.
5Hoogenraad CC, Bradke F Control of neuronal polarity and plasticity--a renaissance for microtubules? Trends CellBiol.2009;19:669-676.
Erturk A, Hellal F, Enes J, Bradke F Disorganized microtubules underlie the formation of retraction bulbs and thefailure of axonal regeneration. J Neurosci.2007;27:9169-9180.
1Yuan J, Yankner BA Apoptosis in the nervous system. Nature.2000;407:802-809.
2Drewes G, Trinczek B, Illenberger S, Biernat J, Schmitt-Ulms G, et al. Microtubule-associated protein/microtubuleaffinity-regulating kinase (p110mark). A novel protein kinase that regulates tau-microtubule interactions and dynamicinstability by phosphorylation at the Alzheimer-specific site serine262. J Biol Chem.1995;270:7679-7688.
3Utton MA, Vandecandelaere A, Wagner U, Reynolds CH, Gibb GM, et al. Phosphorylation of tau by glycogen
synthase kinase3beta affects the ability of tau to promote microtubule self-assembly. Biochem J.1997;323(Pt3):741-747.
4Biernat J, Gustke N, Drewes G, Mandelkow EM, Mandelkow E Phosphorylation of Ser262strongly reduces bindingof tau to microtubules: distinction between PHF-like immunoreactivity and microtubule binding. Neuron.1993;11:153-163.
5Polydoro M, Acker CM, Duff K, Castillo PE, Davies P Age-dependent impairment of cognitive and synaptic functionin the htau mouse model of tau pathology. J Neurosci.2009;29:10741-10749.
6Peng S, Wuu J, Mufson EJ, Fahnestock M Precursor form of brain-derived neurotrophic factor and maturebrain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer's disease. J Neurochem.2005;93:1412-1421.
1Johnson GV, Stoothoff WH Tau phosphorylation in neuronal cell function and dysfunction. J Cell Sci.2004;117:5721-5729.
Liu F, Li B, Tung EJ, Grundke-Iqbal I, Iqbal K, et al. Site-specific effects of tau phosphorylation on its microtubuleassembly activity and self-aggregation. Eur J Neurosci.2007;26:3429-3436.
3Mondragon-Rodriguez S, Mena R, Binder LI, Smith MA, Perry G, et al. Conformational changes and cleavage of tauin Pick bodies parallel the early processing of tau found in Alzheimer pathology. Neuropathol Appl Neurobiol.2008;34:62-75.
4Mondragon-Rodriguez S, Trillaud-Doppia E, Dudilot A, Bourgeois C, Lauzon M, et al. Interaction of endogenous tauprotein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation. J Biol Chem.2012;287:32040-32053.
Ho YS, Yang X, Lau JC, Hung CH, Wuwongse S, et al. Endoplasmic reticulum stress induces tau pathology andforms a vicious cycle: implication in Alzheimer's disease pathogenesis. J Alzheimers Dis.2012;28:839-854.
1Kosik KS, Kowall NW, McKee A Along the way to a neurofibrillary tangle: a look at the structure of tau. Ann Med.1989;21:109-112.
1Greenberg ME, Xu B, Lu B, Hempstead BL New insights in the biology of BDNF synthesis and release: implicationsin CNS function. J Neurosci.2009;29:12764-12767.
2Lu B BDNF and activity-dependent synaptic modulation. Learn Mem.2003;10:86-98.
1Drewes G, Trinczek B, Illenberger S, Biernat J, Schmitt-Ulms G, et al. Microtubule-associated protein/microtubuleaffinity-regulating kinase (p110mark). A novel protein kinase that regulates tau-microtubule interactions and dynamicinstability by phosphorylation at the Alzheimer-specific site serine262. J Biol Chem.1995;270:7679-7688.
2Haque N, Tanaka T, Iqbal K, Grundke-Iqbal I Regulation of expression, phosphorylation and biological activity of tauduring differentiation in SY5Y cells. Brain Res.1999;838:69-77.
3Avila J, Lucas JJ, Perez M, Hernandez F Role of tau protein in both physiological and pathological conditions.Physiol Rev.2004;84:361-384.
Hoogenraad CC, Bradke F Control of neuronal polarity and plasticity--a renaissance for microtubules? Trends CellBiol.2009;19:669-676.
1Morris M, Maeda S, Vossel K, Mucke L The many faces of tau. Neuron.2011;70:410-426.
2Whiteman IT, Minamide LS, Goh de L, Bamburg JR, Goldsbury C Rapid changes in phospho-MAP/tau epitopesduring neuronal stress: cofilin-actin rods primarily recruit microtubule binding domain epitopes. PLoS One.2011;6:e20878.
1Park H, Poo MM Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci.2013;14:27-23.
Cohen-Cory S, Fraser SE Effects of brain-derived neurotrophic factor on optic axon branching and remodelling invivo. Nature.1995;378:192-196.
3Ji Y, Lu Y, Yang F, Shen W, Tang TT, et al. Acute and gradual increases in BDNF concentration elicit distinctsignaling and functions in neurons. Nat Neurosci.2010;13:302-309.
4Tyler WJ, Pozzo-Miller L Miniature synaptic transmission and BDNF modulate dendritic spine growth and form inrat CA1neurones. J Physiol.2003;553:497-509.
5Horch HW, Kruttgen A, Portbury SD, Katz LC Destabilization of cortical dendrites and spines by BDNF. Neuron.1999;23:353-364.
Brandt R, Leger J, Lee G Interaction of tau with the neural plasma membrane mediated by tau's amino-terminalprojection domain. J Cell Biol.1995;131:1327-1340.
1Vasquez RJ, Howell B, Yvon AM, Wadsworth P, Cassimeris L Nanomolar concentrations of nocodazole alter2microtubule dynamic instability in vivo and in vitro. Mol Biol Cell.1997;8:973-985.
Zempel H, Thies E, Mandelkow E, Mandelkow EM Abeta oligomers cause localized Ca(2+) elevation, missorting ofendogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J Neurosci.2010;30:11938-11950.
3Lu B, Nagappan G, Guan X, Nathan PJ, Wren P BDNF-based synaptic repair as a disease-modifying strategy forneurodegenerative diseases. Nat Rev Neurosci.2013;14:401-416.
4Ballatore C, Lee VM, Trojanowski JQ Tau-mediated neurodegeneration in Alzheimer's disease and related disorders.Nat Rev Neurosci.2007;8:663-672.
5Drubin D, Kobayashi S, Kellogg D, Kirschner M Regulation of microtubule protein levels during cellularmorphogenesis in nerve growth factor-treated PC12cells. J Cell Biol.1988;106:1583-1591.
6David DC, Layfield R, Serpell L, Narain Y, Goedert M, et al. Proteasomal degradation of tau protein. J Neurochem.2002;83:176-185.
7Jinwal UK, Trotter JH, Abisambra JF, Koren J,3rd, Lawson LY, et al. The Hsp90kinase co-chaperone Cdc37regulates tau stability and phosphorylation dynamics. J Biol Chem.2011;286:16976-16983.
8Yoshizaki C, Tsukane M, Yamauchi T Overexpression of tau leads to the stimulation of neurite outgrowth, theactivation of caspase3activity, and accumulation and phosphorylation of tau in neuroblastoma cells on cAMP treatment.Neurosci Res.2004;49:363-371.
Sultan A, Nesslany F, Violet M, Begard S, Loyens A, et al. Nuclear tau, a key player in neuronal DNA protection. JBiol Chem.2011;286:4566-4575.
1Strittmatter WJ, Saunders AM, Goedert M, Weisgraber KH, Dong LM, et al. Isoform-specific interactions ofapolipoprotein E with microtubule-associated protein tau: implications for Alzheimer disease. Proc Natl Acad Sci U S A.1994;91:11183-11186.
2Bhaskar K, Yen SH, Lee G Disease-related modifications in tau affect the interaction between Fyn and Tau. J BiolChem.2005;280:35119-35125.
3Dawson HN, Cantillana V, Jansen M, Wang H, Vitek MP, et al. Loss of tau elicits axonal degeneration in a mousemodel of Alzheimer's disease. Neuroscience.2010;169:516-531.
4Morris M, Maeda S, Vossel K, Mucke L The many faces of tau. Neuron.2011;70:410-426.
5Jin M, Shepardson N, Yang T, Chen G, Walsh D, et al. Soluble amyloid beta-protein dimers isolated from Alzheimercortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc Natl Acad Sci U S A.2011;108:5819-5824.
6Zempel H, Thies E, Mandelkow E, Mandelkow EM Abeta oligomers cause localized Ca(2+) elevation, missorting ofendogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J Neurosci.2010;30:11938-11950.
Planel E, Tatebayashi Y, Miyasaka T, Liu L, Wang L, et al. Insulin dysfunction induces in vivo tauhyperphosphorylation through distinct mechanisms. J Neurosci.2007;27:13635-13648.
8Miao Y, Chen J, Zhang Q, Sun A Deletion of tau attenuates heat shock-induced injury in cultured cortical neurons. JNeurosci Res.2010;88:102-110.
9Spires-Jones TL, Stoothoff WH, de Calignon A, Jones PB, Hyman BT Tau pathophysiology in neurodegeneration: atangled issue. Trends Neurosci.2009;32:150-159.
10Noble W, Pooler AM, Hanger DP Advances in tau-based drug discovery. Expert Opin Drug Discov.2011;6:797-810.
Gordon D, Kidd GJ, Smith R Antisense suppression of tau in cultured rat oligodendrocytes inhibits processformation. J Neurosci Res.2008;86:2591-2601.
1Caccamo A, Maldonado MA, Bokov AF, Majumder S, Oddo S CBP gene transfer increases BDNF levels andameliorates learning and memory deficits in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A.2010;107:22687-22692.
2Blurton-Jones M, Kitazawa M, Martinez-Coria H, Castello NA, Muller FJ, et al. Neural stem cells improve cognitionvia BDNF in a transgenic model of Alzheimer disease. Proc Natl Acad Sci U S A.2009;106:13594-13599.
3Encinas M, Iglesias M, Liu Y, Wang H, Muhaisen A, et al. Sequential treatment of SH-SY5Y cells with retinoic acidand brain-derived neurotrophic factor gives rise to fully differentiated, neurotrophic factor-dependent, human neuron-likecells. J Neurochem.2000;75:991-1003.
4Jamsa A, Hasslund K, Cowburn RF, Backstrom A, Vasange M The retinoic acid and brain-derived neurotrophic factordifferentiated SH-SY5Y cell line as a model for Alzheimer's disease-like tau phosphorylation. Biochem Biophys ResCommun.2004;319:993-1000.
5Haque N, Tanaka T, Iqbal K, Grundke-Iqbal I Regulation of expression, phosphorylation and biological activity of tauduring differentiation in SY5Y cells. Brain Res.1999;838:69-77.
6Biernat J, Gustke N, Drewes G, Mandelkow EM, Mandelkow E Phosphorylation of Ser262strongly reduces bindingof tau to microtubules: distinction between PHF-like immunoreactivity and microtubule binding. Neuron.1993;11:153-163.
1Besser R, Kramer G, Thumler R, Bohl J, Gutmann L, et al. Acute trimethyltin limbic-cerebellar syndrome. Neurology.1987;37:945-950.
2Balaban CD, O'Callaghan JP, Billingsley ML Trimethyltin-induced neuronal damage in the rat brain: comparativestudies using silver degeneration stains, immunocytochemistry and immunoassay for neuronotypic and gliotypic proteins.Neuroscience.1988;26:337-361.
3Chang LW, Dyer RS A time-course study of trimethyltin induced neuropathology in rats. Neurobehav Toxicol Teratol.1983;5:443-459.
4Ishikawa K, Kubo T, Shibanoki S, Matsumoto A, Hata H, et al. Hippocampal degeneration inducing impairment oflearning in rats: model of dementia? Behav Brain Res.1997;83:39-44.
5Ishikura N, Tsunashima K, Watanabe K, Nishimura T, Minabe Y, et al. Neuropeptide Y and somatostatin participatedifferently in the seizure-generating mechanisms following trimethyltin-induced hippocampal damage. Neurosci Res.2002;44:237-248.
6Nilsberth C, Kostyszyn B, Luthman J Changes in APP, PS1and other factors related to Alzheimer's diseasepathophysiology after trimethyltin-induced brain lesion in the rat. Neurotox Res.2002;4:625-636.
Boyer IJ Toxicity of dibutyltin, tributyltin and other organotin compounds to humans and to experimental animals.Toxicology.1989;55:253-298.
8Borghi V, Porte C Organotin pollution in deep-sea fish from the northwestern Mediterranean. Environ Sci Technol.2002;36:4224-4228.
9Chang LW The neurotoxicology and pathology of organomercury, organolead, and organotin. J Toxicol Sci.1990;15Suppl4:125-151.
10Yoo CI, Kim Y, Jeong KS, Sim CS, Choy N, et al. A case of acute organotin poisoning. J Occup Health.2007;49:305-310.
Holloway LN, Pannell KH, Whalen MM Effects of a series of triorganotins on ATP levels in human natural killercells. Environ Toxicol Pharmacol.2008;25:43-50.
1Fortemps E, Amand G, Bomboir A, Lauwerys R, Laterre EC Trimethyltin poisoning. Report of two cases. Int ArchOccup Environ Health.1978;41:1-6.
2Ross WD, Emmett EA, Steiner J, Tureen R Neurotoxic effects of occupational exposure to organotins. Am JPsychiatry.1981;138:1092-1095.
3Kreyberg S, Torvik A, Bjorneboe A, Wiik-Larsen W, Jacobsen D Trimethyltin poisoning: report of a case withpostmortem examination. Clin Neuropathol.1992;11:256-259.
4Ghosh BB, Talukder G, Sharma A Frequency of chromosome aberrations induced by trimethyltin chloride in humanperipheral blood lymphocytes in vitro: related to age of donors. Mech Ageing Dev.1991;57:125-137.
5Gomez FD, Apodaca P, Holloway LN, Pannell KH, Whalen MM Effect of a series of triorganotins on the immunefunction of human natural killer cells. Environ Toxicol Pharmacol.2007;23:18-24.
6Ohno H, Suzuki M, Nakashima S, Aoyama T, Mitani K [Determination of organotin compounds in plastic productsby GC/MS after ethyl derivatization with sodium tetraethylborate]. Shokuhin Eiseigaku Zasshi.2002;43:208-214.
7Fent K Ecotoxicology of organotin compounds. Crit Rev Toxicol.1996;26:1-117.
8Holloway LN, Pannell KH, Whalen MM Effects of a series of triorganotins on ATP levels in human natural killercells. Environ Toxicol Pharmacol.2008;25:43-50.
9Teuten EL, Saquing JM, Knappe DR, Barlaz MA, Jonsson S, et al. Transport and release of chemicals from plastics tothe environment and to wildlife. Philos Trans R Soc Lond B Biol Sci.2009;364:2027-2045.
10Vajda FJ Neuroprotection and neurodegenerative disease. J Clin Neurosci.2002;9:4-8.
11Mattson MP Glutamate and neurotrophic factors in neuronal plasticity and disease. Ann N Y Acad Sci.2008;1144:97-112.
12Minghetti L Role of inflammation in neurodegenerative diseases. Curr Opin Neurol.2005;18:315-321.
1Parent JM Injury-induced neurogenesis in the adult mammalian brain. Neuroscientist.2003;9:261-272.
2Geloso MC, Corvino V, Michetti F Trimethyltin-induced hippocampal degeneration as a tool to investigateneurodegenerative processes. Neurochem Int.2011;58:729-738.
3Chang LW, Wenger GR, McMillan DE, Dyer RS Species and strain comparison of acute neurotoxic effects oftrimethyltin in mice and rats. Neurobehav Toxicol Teratol.1983;5:337-350.
4Harry GJ, Lefebvre d'Hellencourt C Dentate gyrus: alterations that occur with hippocampal injury. Neurotoxicology.2003;24:343-356.
5Geloso MC, Corvino V, Michetti F Trimethyltin-induced hippocampal degeneration as a tool to investigateneurodegenerative processes. Neurochem Int.2011;58:729-738.
6Balaban CD, O'Callaghan JP, Billingsley ML Trimethyltin-induced neuronal damage in the rat brain: comparativestudies using silver degeneration stains, immunocytochemistry and immunoassay for neuronotypic and gliotypic proteins.Neuroscience.1988;26:337-361.
Kreyberg S, Torvik A, Bjorneboe A, Wiik-Larsen W, Jacobsen D Trimethyltin poisoning: report of a case withpostmortem examination. Clin Neuropathol.1992;11:256-259.
1Misiti F, Orsini F, Clementi ME, Lattanzi W, Giardina B, et al. Mitochondrial oxygen consumption inhibitionimportance for TMT-dependent cell death in undifferentiated PC12cells. Neurochem Int.2008;52:1092-1099.
2Billingsley ML, Yun J, Reese BE, Davidson CE, Buck-Koehntop BA, et al. Functional and structural properties ofstannin: roles in cellular growth, selective toxicity, and mitochondrial responses to injury. J Cell Biochem.2006;98:243-250.
3Piacentini R, Gangitano C, Ceccariglia S, Del Fa A, Azzena GB, et al. Dysregulation of intracellular calciumhomeostasis is responsible for neuronal death in an experimental model of selective hippocampal degeneration inducedby trimethyltin. J Neurochem.2008;105:2109-2121.
4Ceccariglia S, D'Altocolle A, Del Fa A, Pizzolante F, Caccia E, et al. Cathepsin D plays a crucial role in thetrimethyltin-induced hippocampal neurodegeneration process. Neuroscience.174:160-170.
5Casalbore P, Barone I, Felsani A, D'Agnano I, Michetti F, et al. Neural stem cells modified to express BDNFantagonize trimethyltin-induced neurotoxicity through PI3K/Akt and MAP kinase pathways. J Cell Physiol.2010;224:710-721.
6Andersson H, Wetmore C, Lindqvist E, Luthman J, Olson L Trimethyltin exposure in the rat induces delayed changesin brain-derived neurotrophic factor, fos and heat shock protein70. Neurotoxicology.1997;18:147-159.
7Cohen-Cory S, Fraser SE Effects of brain-derived neurotrophic factor on optic axon branching and remodelling invivo. Nature.1995;378:192-196.
8McAllister AK, Lo DC, Katz LC Neurotrophins regulate dendritic growth in developing visual cortex. Neuron.1995;15:791-803.
Ji Y, Lu Y, Yang F, Shen W, Tang TT, et al. Acute and gradual increases in BDNF concentration elicit distinctsignaling and functions in neurons. Nat Neurosci.2010;13:302-309.
1Tartaglia N, Du J, Tyler WJ, Neale E, Pozzo-Miller L, et al. Protein synthesis-dependent and-independent regulationof hippocampal synapses by brain-derived neurotrophic factor. J Biol Chem.2001;276:37585-37593.
2Horch HW, Kruttgen A, Portbury SD, Katz LC Destabilization of cortical dendrites and spines by BDNF. Neuron.1999;23:353-364.
3Pozzo-Miller LD, Gottschalk W, Zhang L, McDermott K, Du J, et al. Impairments in high-frequency transmission,synaptic vesicle docking, and synaptic protein distribution in the hippocampus of BDNF knockout mice. J Neurosci.1999;19:4972-4983.
4Otal R, Martinez A, Soriano E Lack of TrkB and TrkC signaling alters the synaptogenesis and maturation of mossyfiber terminals in the hippocampus. Cell Tissue Res.2005;319:349-358.
5Aguado F, Carmona MA, Pozas E, Aguilo A, Martinez-Guijarro FJ, et al. BDNF regulates spontaneous correlatedactivity at early developmental stages by increasing synaptogenesis and expression of the K+/Cl-co-transporter KCC2.Development.2003;130:1267-1280.
6Singh B, Henneberger C, Betances D, Arevalo MA, Rodriguez-Tebar A, et al. Altered balance ofglutamatergic/GABAergic synaptic input and associated changes in dendrite morphology after BDNF expression inBDNF-deficient hippocampal neurons. J Neurosci.2006;26:7189-7200.
7Tanaka J, Horiike Y, Matsuzaki M, Miyazaki T, Ellis-Davies GC, et al. Protein synthesis and neurotrophin-dependentstructural plasticity of single dendritic spines. Science.2008;319:1683-1687.
8Ma YL, Wang HL, Wu HC, Wei CL, Lee EH Brain-derived neurotrophic factor antisense oligonucleotide impairsmemory retention and inhibits long-term potentiation in rats. Neuroscience.1998;82:957-967.
Alonso M, Vianna MR, Izquierdo I, Medina JH Signaling mechanisms mediating BDNF modulation of memoryformation in vivo in the hippocampus. Cell Mol Neurobiol.2002;22:663-674.
1Nagahara AH, Tuszynski MH Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat RevDrug Discov.2011;10:209-219.
Kemppainen S, Rantamaki T, Jeronimo-Santos A, Lavasseur G, Autio H, et al. Impaired TrkB receptor signalingcontributes to memory impairment in APP/PS1mice. Neurobiol Aging.2012;33:1122e1123-1139.
3Nagahara AH, Merrill DA, Coppola G, Tsukada S, Schroeder BE, et al. Neuroprotective effects of brain-derivedneurotrophic factor in rodent and primate models of Alzheimer's disease. Nat Med.2009;15:331-337.
4Minghetti L Role of inflammation in neurodegenerative diseases. Curr Opin Neurol.2005;18:315-321.
5Kraft AD, McPherson CA, Harry GJ Heterogeneity of microglia and TNF signaling as determinants for neuronaldeath or survival. Neurotoxicology.2009;30:785-793.
6Tran HY, Shin EJ, Saito K, Nguyen XK, Chung YH, et al. Protective potential of IL-6against trimethyltin-inducedneurotoxicity in vivo. Free Radic Biol Med.2012;52:1159-1174.
7Jean Harry G, Bruccoleri A, Lefebvre d'Hellencourt C Differential modulation of hippocampal chemical-inducedinjury response by ebselen, pentoxifylline, and TNFalpha-, IL-1alpha-, and IL-6-neutralizing antibodies. J Neurosci Res.2003;73:526-536.
8Brabeck C, Michetti F, Geloso MC, Corvino V, Goezalan F, et al. Expression of EMAP-II by activatedmonocytes/microglial cells in different regions of the rat hippocampus after trimethyltin-induced brain damage. ExpNeurol.2002;177:341-346.
9Little AR, Miller DB, Li S, Kashon ML, O'Callaghan JP Trimethyltin-induced neurotoxicity: gene expressionpathway analysis, q-RT-PCR and immunoblotting reveal early effects associated with hippocampal damage and gliosis.Neurotoxicol Teratol.2012;34:72-82.
1Liu Y, Imai H, Sadamatsu M, Tsunashima K, Kato N Cytokines participate in neuronal death induced by trimethyltin
2in the rat hippocampus via type II glucocorticoid receptors. Neurosci Res.2005;51:319-327.Corvino V, Marchese E, Zarkovic N, Zarkovic K, Cindric M, et al. Distribution and time-course of4-hydroxynonenal,heat shock protein110/105family members and cyclooxygenase-2expression in the hippocampus of rat duringtrimethyltin-induced neurodegeneration. Neurochem Res.2011;36:1490-1500.
3Allaman I, Belanger M, Magistretti PJ Astrocyte-neuron metabolic relationships: for better and for worse. TrendsNeurosci.2011;34:76-87.
4Zarkovic N, Zarkovic K, Schaur RJ, Stolc S, Schlag G, et al.4-Hydroxynonenal as a second messenger of freeradicals and growth modifying factor. Life Sci.1999;65:1901-1904.
56Coyle JT, Puttfarcken P Oxidative stress, glutamate, and neurodegenerative disorders. Science.1993;262:689-695.Schulz JB, Lindenau J, Seyfried J, Dichgans J Glutathione, oxidative stress and neurodegeneration. Eur J Biochem.2000;267:4904-4911.
7Ali SF, LeBel CP, Bondy SC Reactive oxygen species formation as a biomarker of methylmercury and trimethyltinneurotoxicity. Neurotoxicology.1992;13:637-648.
8Shin EJ, Suh SK, Lim YK, Jhoo WK, Hjelle OP, et al. Ascorbate attenuates trimethyltin-induced oxidative burdenand neuronal degeneration in the rat hippocampus by maintaining glutathione homeostasis. Neuroscience.2005;133:715-727.
9Haddad el B, McCluskie K, Birrell MA, Dabrowski D, Pecoraro M, et al. Differential effects of ebselen on neutrophilrecruitment, chemokine, and inflammatory mediator expression in a rat model of lipopolysaccharide-induced pulmonaryinflammation. J Immunol.2002;169:974-982.
1Haddad el B, McCluskie K, Birrell MA, Dabrowski D, Pecoraro M, et al. Differential effects of ebselen on neutrophilrecruitment, chemokine, and inflammatory mediator expression in a rat model of lipopolysaccharide-induced pulmonaryinflammation. J Immunol.2002;169:974-982.
2Koizumi H, Fujisawa H, Suehiro E, Shirao S, Suzuki M Neuroprotective effects of ebselen following forebrain3ischemia: involvement of glutamate and nitric oxide. Neurol Med Chir (Tokyo).2011;51:337-343.
Block ML, Hong JS Microglia and inflammation-mediated neurodegeneration: multiple triggers with a commonmechanism. Prog Neurobiol.2005;76:77-98.
4Straiko MM, Gudelsky GA, Coolen LM, Harrison R, Zemlan FP Treatment with trimethyltin promotes the formationof cleaved tau in the rat brain. J Neurosci Res.2006;84:1116-1123.
5Farias G, Cornejo A, Jimenez J, Guzman L, Maccioni RB Mechanisms of tau self-aggregation and neurotoxicity. CurrAlzheimer Res.2011;8:608-614.
6Hanger DP, Anderton BH, Noble W Tau phosphorylation: the therapeutic challenge for neurodegenerative disease.Trends Mol Med.2009;15:112-119.
Liu F, Li B, Tung EJ, Grundke-Iqbal I, Iqbal K, et al. Site-specific effects of tau phosphorylation on its microtubuleassembly activity and self-aggregation. Eur J Neurosci.2007;26:3429-3436.
1Mondragon-Rodriguez S, Mena R, Binder LI, Smith MA, Perry G, et al. Conformational changes and cleavage of tauin Pick bodies parallel the early processing of tau found in Alzheimer pathology. Neuropathol Appl Neurobiol.2008;34:62-75.
2Mondragon-Rodriguez S, Trillaud-Doppia E, Dudilot A, Bourgeois C, Lauzon M, et al. Interaction of endogenous tauprotein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation. J Biol Chem.2012;287:32040-32053.
Ho YS, Yang X, Lau JC, Hung CH, Wuwongse S, et al. Endoplasmic reticulum stress induces tau pathology andforms a vicious cycle: implication in Alzheimer's disease pathogenesis. J Alzheimers Dis.2012;28:839-854.
4Kim SU, de Vellis J Stem cell-based cell therapy in neurological diseases: a review. J Neurosci Res.2009;87:2183-2200.
5Woodruff ML, Baisden RH, Nonneman AJ Anatomical and behavioral sequelae of fetal brain transplants in rats withtrimethyltin-induced neurodegeneration. Neurotoxicology.1991;12:427-444.
6Roy A, Agrawal AK, Husain R, Dubey MP, Seth PK Cholinergic and serotonergic alterations in the rat hippocampusfollowing trimethyltin exposure and fetal neural transplantation. Neurosci Lett.1999;259:173-176.
Yoneyama M, Seko K, Kawada K, Sugiyama C, Ogita K High susceptibility of cortical neural progenitor cells totrimethyltin toxicity: involvement of both caspases and calpain in cell death. Neurochem Int.2009;55:257-264.
1Martino G, Pluchino S, Bonfanti L, Schwartz M Brain regeneration in physiology and pathology: the immunesignature driving therapeutic plasticity of neural stem cells. Physiol Rev.2011;91:1281-1304.
2Parent JM Injury-induced neurogenesis in the adult mammalian brain. Neuroscientist.2003;9:261-272.
Corvino V, Geloso MC, Cavallo V, Guadagni E, Passalacqua R, et al. Enhanced neurogenesis duringtrimethyltin-induced neurodegeneration in the hippocampus of the adult rat. Brain Res Bull.2005;65:471-477.
4McPherson CA, Aoyama M, Harry GJ Interleukin (IL)-1and IL-6regulation of neural progenitor cell proliferationwith hippocampal injury: differential regulatory pathways in the subgranular zone (SGZ) of the adolescent and maturemouse brain. Brain Behav Immun.2011;25:850-862.
5Gray WP Neuropeptide Y signalling on hippocampal stem cells in health and disease. Mol Cell Endocrinol.2008;288:52-62.
6Corvino V, Marchese E, Giannetti S, Lattanzi W, Bonvissuto D, et al. The neuroprotective and neurogenic effects ofneuropeptide Y administration in an animal model of hippocampal neurodegeneration and temporal lobe epilepsy inducedby trimethyltin. J Neurochem.2012;122:415-426.
[1] Geloso MC, Corvino V, Michetti F Trimethyltin-induced hippocampal degenerationas a tool to investigate neurodegenerative processes. Neurochem Int.2011;58:729-738.
[2] Chang LW, Wenger GR, McMillan DE, Dyer RS Species and strain comparison ofacute neurotoxic effects of trimethyltin in mice and rats. Neurobehav Toxicol Teratol.1983;5:337-350.
[3] Harry GJ, Lefebvre d'Hellencourt C Dentate gyrus: alterations that occur withhippocampal injury. Neurotoxicology.2003;24:343-356.
[4] Balaban CD, O'Callaghan JP, Billingsley ML Trimethyltin-induced neuronal damagein the rat brain: comparative studies using silver degeneration stains,immunocytochemistry and immunoassay for neuronotypic and gliotypic proteins.Neuroscience.1988;26:337-361.
[5] Andersson H, Wetmore C, Lindqvist E, Luthman J, Olson L Trimethyltin exposure inthe rat induces delayed changes in brain-derived neurotrophic factor, fos and heatshock protein70. Neurotoxicology.1997;18:147-159.
[6] Casalbore P, Barone I, Felsani A, D'Agnano I, Michetti F, et al. Neural stem cellsmodified to express BDNF antagonize trimethyltin-induced neurotoxicity throughPI3K/Akt and MAP kinase pathways. J Cell Physiol.2010;224:710-721.
[7] Greenberg ME, Xu B, Lu B, Hempstead BL New insights in the biology of BDNFsynthesis and release: implications in CNS function. J Neurosci.2009;29:12764-12767.
[8] Kang H, Schuman EM A requirement for local protein synthesis inneurotrophin-induced hippocampal synaptic plasticity. Science.1996;273:1402-1406.
[9] Gonzalez-Billault C, Engelke M, Jimenez-Mateos EM, Wandosell F, Caceres A, et al.Participation of structural microtubule-associated proteins (MAPs) in the developmentof neuronal polarity. J Neurosci Res.2002;67:713-719.
[10] Avila J, Lucas JJ, Perez M, Hernandez F Role of tau protein in both physiologicaland pathological conditions. Physiol Rev.2004;84:361-384.
[11] Hernandez F, Lucas JJ, Cuadros R, Avila J GSK-3dependent phosphoepitopesrecognized by PHF-1and AT-8antibodies are present in different tau isoforms.Neurobiol Aging.2003;24:1087-1094.
[12] Hoogenraad CC, Bradke F Control of neuronal polarity and plasticity--a renaissancefor microtubules? Trends Cell Biol.2009;19:669-676.
[13] Peng S, Wuu J, Mufson EJ, Fahnestock M Precursor form of brain-derivedneurotrophic factor and mature brain-derived neurotrophic factor are decreased in thepre-clinical stages of Alzheimer's disease. J Neurochem.2005;93:1412-1421.
[14] Fulga TA, Elson-Schwab I, Khurana V, Steinhilb ML, Spires TL, et al. Abnormalbundling and accumulation of F-actin mediates tau-induced neuronal degeneration invivo. Nat Cell Biol.2007;9:139-148.
[15] Brunden KR, Trojanowski JQ, Lee VM Advances in tau-focused drug discovery forAlzheimer's disease and related tauopathies. Nat Rev Drug Discov.2009;8:783-793.
[16] Wang JZ, Liu F Microtubule-associated protein tau in development, degeneration andprotection of neurons. Prog Neurobiol.2008;85:148-175.
[17] Spires-Jones TL, Stoothoff WH, de Calignon A, Jones PB, Hyman BT Taupathophysiology in neurodegeneration: a tangled issue. Trends Neurosci.2009;32:150-159.
[18] Vega IE, Hamano T, Propost JA, Grenningloh G, Yen SH Taxol and tauoverexpression induced calpain-dependent degradation of the microtubule-destabilizing protein SCG10. Exp Neurol.2006;202:152-160.
[19] Niewiadomska G, Baksalerska-Pazera M, Riedel G Altered cellular distribution ofphospho-tau proteins coincides with impaired retrograde axonal transport in neurons ofaged rats. Ann N Y Acad Sci.2005;1048:287-295.
[20] Zhang B, Maiti A, Shively S, Lakhani F, McDonald-Jones G, et al.Microtubule-binding drugs offset tau sequestration by stabilizing microtubules andreversing fast axonal transport deficits in a tauopathy model. Proc Natl Acad Sci U S A.2005;102:227-231.
[21] Rapoport M, Dawson HN, Binder LI, Vitek MP, Ferreira A Tau is essential to beta-amyloid-induced neurotoxicity. Proc Natl Acad Sci U S A.2002;99:6364-6369.
[22] Morris M, Maeda S, Vossel K, Mucke L The many faces of tau. Neuron.2011;70:410-426.
[23] Wolfe MS Tau mutations in neurodegenerative diseases. J Biol Chem.2009;284:6021-6025.
[24] Papanikolopoulou K, Kosmidis S, Grammenoudi S, Skoulakis EM Phosphorylationdifferentiates tau-dependent neuronal toxicity and dysfunction. Biochem Soc Trans.2010;38:981-987.
[25] Liu L, Drouet V, Wu JW, Witter MP, Small SA, et al. Trans-synaptic spread of taupathology in vivo. PLoS One.2012;7: e31302.
[26] Nagahara AH, Tuszynski MH Potential therapeutic uses of BDNF in neurologicaland psychiatric disorders. Nat Rev Drug Discov.2011;10:209-219.
[27] Figiel I, Fiedorowicz A Trimethyltin-evoked neuronal apoptosis and glia response inmixed cultures of rat hippocampal dentate gyrus: a new model for the study of the celltype-specific influence of neurotoxins. Neurotoxicology.2002;23:77-86.
[28] Aksamitiene E, Kiyatkin A, Kholodenko BN Cross-talk between mitogenicRas/MAPK and survival PI3K/Akt pathways: a fine balance. Biochem Soc Trans.2012;40:139-146.
[29] Qing Y, Liang Y, Du Q, Fan P, Xu H, et al. Apoptosis induced by trimethyltinchloride in human neuroblastoma cells SY5Y is regulated by a balance and cross-talkbetween NF-kappaB and MAPKs signaling pathways. Arch Toxicol.87:1273-1285.
[30] Tran HY, Shin EJ, Saito K, Nguyen XK, Chung YH, et al. Protective potential ofIL-6against trimethyltin-induced neurotoxicity in vivo. Free Radic Biol Med.52:1159-1174.
[31] Dopp E, Hartmann LM, von Recklinghausen U, Florea AM, Rabieh S, et al. Thecyto-and genotoxicity of organotin compounds is dependent on the cellular uptakecapability. Toxicology.2007;232:226-234.
[32] Piacentini R, Gangitano C, Ceccariglia S, Del Fa A, Azzena GB, et al. Dysregulationof intracellular calcium homeostasis is responsible for neuronal death in anexperimental model of selective hippocampal degeneration induced by trimethyltin. JNeurochem.2008;105:2109-2121.
[33] Zhang L, Li L, Prabhakaran K, Borowitz JL, Isom GE Trimethyltin-inducedapoptosis is associated with upregulation of inducible nitric oxide synthase and Bax ina hippocampal cell line. Toxicol Appl Pharmacol.2006;216:34-43.
[34] Duchen MR Mitochondria, calcium-dependent neuronal death and neurodegenerativedisease. Pflugers Arch.464:111-121.
[35] Cai J, Wang M, Li B, Wang C, Chen Y, et al. Apoptotic and necrotic actionmechanisms of trimethyltin in human hepatoma G2(HepG2) cells. Chem Res Toxicol.2009;22:1582-1587.
[36] Geloso MC, Vercelli A, Corvino V, Repici M, Boca M, et al. Cyclooxygenase-2andcaspase3expression in trimethyltin-induced apoptosis in the mouse hippocampus. ExpNeurol.2002;175:152-160.
[37] Minghetti L Role of inflammation in neurodegenerative diseases. Curr Opin Neurol.2005;18:315-321.
[38] Lu B, Nagappan G, Guan X, Nathan PJ, Wren P BDNF-based synaptic repair as adisease-modifying strategy for neurodegenerative diseases. Nat Rev Neurosci.2013;14:401-416.
[39] Koda T, Kuroda Y, Imai H Protective effect of rutin against spatial memoryimpairment induced by trimethyltin in rats. Nutr Res.2008;28:629-634.
[40] Koda T, Kuroda Y, Imai H Rutin supplementation in the diet has protective effectsagainst toxicant-induced hippocampal injury by suppression of microglial activationand pro-inflammatory cytokines: protective effect of rutin against toxicant-inducedhippocampal injury. Cell Mol Neurobiol.2009;29:523-531.
[41] Kim JK, Bae H, Kim MJ, Choi SJ, Cho HY, et al. Inhibitory effect of Poncirustrifoliate on acetylcholinesterase and attenuating activity against trimethyltin-inducedlearning and memory impairment. Biosci Biotechnol Biochem.2009;73:1105-1112.
[42] Czlonkowska A, Kurkowska-Jastrzebska I Inflammation and gliosis in neurologicaldiseases--clinical implications. J Neuroimmunol.2011;231:78-85.
[43] Funk JA, Gohlke J, Kraft AD, McPherson CA, Collins JB, et al. Voluntary exerciseprotects hippocampal neurons from trimethyltin injury: possible role of interleukin-6tomodulate tumor necrosis factor receptor-mediated neurotoxicity. Brain Behav Immun.2011;25:1063-1077.
[44] Shuto M, Higuchi K, Sugiyama C, Yoneyama M, Kuramoto N, et al. Endogenous andexogenous glucocorticoids prevent trimethyltin from causing neuronal degeneration ofthe mouse brain in vivo: involvement of oxidative stress pathways. J Pharmacol Sci.2009;110:424-436.
[45] Shin EJ, Suh SK, Lim YK, Jhoo WK, Hjelle OP, et al. Ascorbate attenuatestrimethyltin-induced oxidative burden and neuronal degeneration in the rathippocampus by maintaining glutathione homeostasis. Neuroscience.2005;133:715-727.
[46] Arancio O, Chao MV Neurotrophins, synaptic plasticity and dementia. Curr OpinNeurobiol.2007;17:325-330.
[47] Bhatt DH, Zhang S, Gan WB Dendritic spine dynamics. Annu Rev Physiol.2009;71:261-282.
[48] Hemmings BA Akt signaling: linking membrane events to life and death decisions.Science.1997;275:628-630.
[49] Impey S, Obrietan K, Storm DR Making new connections: role of ERK/MAP kinasesignaling in neuronal plasticity. Neuron.1999;23:11-14.
[50] Dent P Crosstalk between ERK, AKT, and cell survival. Cancer Biol Ther.2014;15:245-246.
[51] Caceres A, Kosik KS Inhibition of neurite polarity by tau antisense oligonucleotidesin primary cerebellar neurons. Nature.1990;343:461-463.
[52] Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW A protein factor essentialfor microtubule assembly. Proc Natl Acad Sci U S A.1975;72:1858-1862.
[53] Thies E, Mandelkow EM Missorting of tau in neurons causes degeneration ofsynapses that can be rescued by the kinase MARK2/Par-1. J Neurosci.2007;27:2896-2907.
[54] Dickstein DL, Brautigam H, Stockton SD, Jr., Schmeidler J, Hof PR Changes indendritic complexity and spine morphology in transgenic mice expressing humanwild-type tau. Brain Struct Funct.2010;214:161-179.
[55] Eckermann K, Mocanu MM, Khlistunova I, Biernat J, Nissen A, et al. Thebeta-propensity of Tau determines aggregation and synaptic loss in inducible mousemodels of tauopathy. J Biol Chem.2007;282:31755-31765.
[56] Jaworski J, Kapitein LC, Gouveia SM, Dortland BR, Wulf PS, et al. Dynamicmicrotubules regulate dendritic spine morphology and synaptic plasticity. Neuron.2009;61:85-100.
[57] Erturk A, Hellal F, Enes J, Bradke F Disorganized microtubules underlie theformation of retraction bulbs and the failure of axonal regeneration. J Neurosci.2007;27:9169-9180.
[58] Yuan J, Yankner BA Apoptosis in the nervous system. Nature.2000;407:802-809.
[59] Drewes G, Trinczek B, Illenberger S, Biernat J, Schmitt-Ulms G, et al.Microtubule-associated protein/microtubule affinity-regulating kinase (p110mark). Anovel protein kinase that regulates tau-microtubule interactions and dynamic instabilityby phosphorylation at the Alzheimer-specific site serine262. J Biol Chem.1995;270:7679-7688.
[60] Utton MA, Vandecandelaere A, Wagner U, Reynolds CH, Gibb GM, et al.Phosphorylation of tau by glycogen synthase kinase3beta affects the ability of tau topromote microtubule self-assembly. Biochem J.1997;323(Pt3):741-747.
[61] Biernat J, Gustke N, Drewes G, Mandelkow EM, Mandelkow E Phosphorylation ofSer262strongly reduces binding of tau to microtubules: distinction between PHF-likeimmunoreactivity and microtubule binding. Neuron.1993;11:153-163.
[62] Polydoro M, Acker CM, Duff K, Castillo PE, Davies P Age-dependent impairment ofcognitive and synaptic function in the htau mouse model of tau pathology. J Neurosci.2009;29:10741-10749.
[63] Johnson GV, Stoothoff WH Tau phosphorylation in neuronal cell function anddysfunction. J Cell Sci.2004;117:5721-5729.
[64] Liu F, Li B, Tung EJ, Grundke-Iqbal I, Iqbal K, et al. Site-specific effects of tauphosphorylation on its microtubule assembly activity and self-aggregation. Eur JNeurosci.2007;26:3429-3436.
[65] Mondragon-Rodriguez S, Mena R, Binder LI, Smith MA, Perry G, et al.Conformational changes and cleavage of tau in Pick bodies parallel the earlyprocessing of tau found in Alzheimer pathology. Neuropathol Appl Neurobiol.2008;34:62-75.
[66] Mondragon-Rodriguez S, Trillaud-Doppia E, Dudilot A, Bourgeois C, Lauzon M, et al.Interaction of endogenous tau protein with synaptic proteins is regulated byN-methyl-D-aspartate receptor-dependent tau phosphorylation. J Biol Chem.2012;287:32040-32053.
[67] Ho YS, Yang X, Lau JC, Hung CH, Wuwongse S, et al. Endoplasmic reticulum stressinduces tau pathology and forms a vicious cycle: implication in Alzheimer's diseasepathogenesis. J Alzheimers Dis.2012;28:839-854.
[68] Kosik KS, Kowall NW, McKee A Along the way to a neurofibrillary tangle: a look atthe structure of tau. Ann Med.1989;21:109-112.
[69] Lu B BDNF and activity-dependent synaptic modulation. Learn Mem.2003;10:86-98.
[70] Haque N, Tanaka T, Iqbal K, Grundke-Iqbal I Regulation of expression,phosphorylation and biological activity of tau during differentiation in SY5Y cells.Brain Res.1999;838:69-77.
[71] Whiteman IT, Minamide LS, Goh de L, Bamburg JR, Goldsbury C Rapid changes inphospho-MAP/tau epitopes during neuronal stress: cofilin-actin rods primarily recruitmicrotubule binding domain epitopes. PLoS One.2011;6: e20878.
[72] Park H, Poo MM Neurotrophin regulation of neural circuit development and function.Nat Rev Neurosci.2013;14:7-23.
[73] Cohen-Cory S, Fraser SE Effects of brain-derived neurotrophic factor on optic axonbranching and remodelling in vivo. Nature.1995;378:192-196.
[74] Ji Y, Lu Y, Yang F, Shen W, Tang TT, et al. Acute and gradual increases in BDNFconcentration elicit distinct signaling and functions in neurons. Nat Neurosci.2010;13:302-309.
[75] Tyler WJ, Pozzo-Miller L Miniature synaptic transmission and BDNF modulatedendritic spine growth and form in rat CA1neurones. J Physiol.2003;553:497-509.
[76] Horch HW, Kruttgen A, Portbury SD, Katz LC Destabilization of cortical dendritesand spines by BDNF. Neuron.1999;23:353-364.
[77] Brandt R, Leger J, Lee G Interaction of tau with the neural plasma membranemediated by tau's amino-terminal projection domain. J Cell Biol.1995;131:1327-1340.
[78] Vasquez RJ, Howell B, Yvon AM, Wadsworth P, Cassimeris L Nanomolarconcentrations of nocodazole alter microtubule dynamic instability in vivo and in vitro.Mol Biol Cell.1997;8:973-985.
[79] Zempel H, Thies E, Mandelkow E, Mandelkow EM Abeta oligomers cause localizedCa(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation,and destruction of microtubules and spines. J Neurosci.2010;30:11938-11950.
[80] Ballatore C, Lee VM, Trojanowski JQ Tau-mediated neurodegeneration inAlzheimer's disease and related disorders. Nat Rev Neurosci.2007;8:663-672.
[81] Drubin D, Kobayashi S, Kellogg D, Kirschner M Regulation of microtubule proteinlevels during cellular morphogenesis in nerve growth factor-treated PC12cells. J CellBiol.1988;106:1583-1591.
[82] David DC, Layfield R, Serpell L, Narain Y, Goedert M, et al. Proteasomaldegradation of tau protein. J Neurochem.2002;83:176-185.
[83] Jinwal UK, Trotter JH, Abisambra JF, Koren J,3rd, Lawson LY, et al. The Hsp90kinase co-chaperone Cdc37regulates tau stability and phosphorylation dynamics. JBiol Chem.2011;286:16976-16983.
[84] Yoshizaki C, Tsukane M, Yamauchi T Overexpression of tau leads to the stimulationof neurite outgrowth, the activation of caspase3activity, and accumulation andphosphorylation of tau in neuroblastoma cells on cAMP treatment. Neurosci Res.2004;49:363-371.
[85] Sultan A, Nesslany F, Violet M, Begard S, Loyens A, et al. Nuclear tau, a key playerin neuronal DNA protection. J Biol Chem.2011;286:4566-4575.
[86] Strittmatter WJ, Saunders AM, Goedert M, Weisgraber KH, Dong LM, et al.Isoform-specific interactions of apolipoprotein E with microtubule-associated proteintau: implications for Alzheimer disease. Proc Natl Acad Sci U S A.1994;91:11183-11186.
[87] Bhaskar K, Yen SH, Lee G Disease-related modifications in tau affect the interactionbetween Fyn and Tau. J Biol Chem.2005;280:35119-35125.
[88] Dawson HN, Cantillana V, Jansen M, Wang H, Vitek MP, et al. Loss of tau elicitsaxonal degeneration in a mouse model of Alzheimer's disease. Neuroscience.2010;169:516-531.
[89] Jin M, Shepardson N, Yang T, Chen G, Walsh D, et al. Soluble amyloid beta-proteindimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation andneuritic degeneration. Proc Natl Acad Sci U S A.2011;108:5819-5824.
[90] Planel E, Tatebayashi Y, Miyasaka T, Liu L, Wang L, et al. Insulin dysfunctioninduces in vivo tau hyperphosphorylation through distinct mechanisms. J Neurosci.2007;27:13635-13648.
[91] Miao Y, Chen J, Zhang Q, Sun A Deletion of tau attenuates heat shock-induced injuryin cultured cortical neurons. J Neurosci Res.2010;88:102-110.
[92] Noble W, Pooler AM, Hanger DP Advances in tau-based drug discovery. Expert OpinDrug Discov.2011;6:797-810.
[93] Gordon D, Kidd GJ, Smith R Antisense suppression of tau in cultured ratoligodendrocytes inhibits process formation. J Neurosci Res.2008;86:2591-2601.
[94] Caccamo A, Maldonado MA, Bokov AF, Majumder S, Oddo S CBP gene transferincreases BDNF levels and ameliorates learning and memory deficits in a mousemodel of Alzheimer's disease. Proc Natl Acad Sci U S A.2010;107:22687-22692.
[95] Blurton-Jones M, Kitazawa M, Martinez-Coria H, Castello NA, Muller FJ, et al.Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimerdisease. Proc Natl Acad Sci U S A.2009;106:13594-13599.
[96] Encinas M, Iglesias M, Liu Y, Wang H, Muhaisen A, et al. Sequential treatment ofSH-SY5Y cells with retinoic acid and brain-derived neurotrophic factor gives rise tofully differentiated, neurotrophic factor-dependent, human neuron-like cells. JNeurochem.2000;75:991-1003.
[97] Jamsa A, Hasslund K, Cowburn RF, Backstrom A, Vasange M The retinoic acid andbrain-derived neurotrophic factor differentiated SH-SY5Y cell line as a model forAlzheimer's disease-like tau phosphorylation. Biochem Biophys Res Commun.2004;319:993-1000.
[1] Besser R, Kramer G, Thumler R, Bohl J, Gutmann L, et al. Acute trimethyltinlimbic-cerebellar syndrome. Neurology.1987;37:945-950.
[2] Balaban CD, O'Callaghan JP, Billingsley ML Trimethyltin-induced neuronaldamage in the rat brain: comparative studies using silver degeneration stains,immunocytochemistry and immunoassay for neuronotypic and gliotypic proteins.Neuroscience.1988;26:337-361.
[3] Chang LW, Dyer RS A time-course study of trimethyltin induced neuropathology inrats. Neurobehav Toxicol Teratol.1983;5:443-459.
[4] Ishikawa K, Kubo T, Shibanoki S, Matsumoto A, Hata H, et al. Hippocampaldegeneration inducing impairment of learning in rats: model of dementia? BehavBrain Res.1997;83:39-44.
[5] Ishikura N, Tsunashima K, Watanabe K, Nishimura T, Minabe Y, et al. NeuropeptideY and somatostatin participate differently in the seizure-generating mechanismsfollowing trimethyltin-induced hippocampal damage. Neurosci Res.2002;44:237-248.
[6] Nilsberth C, Kostyszyn B, Luthman J Changes in APP, PS1and other factors relatedto Alzheimer's disease pathophysiology after trimethyltin-induced brain lesion in therat. Neurotox Res.2002;4:625-636.
[7] Boyer IJ Toxicity of dibutyltin, tributyltin and other organotin compounds tohumans and to experimental animals. Toxicology.1989;55:253-298.
[8] Borghi V, Porte C Organotin pollution in deep-sea fish from the northwesternMediterranean. Environ Sci Technol.2002;36:4224-4228.
[9] Chang LW The neurotoxicology and pathology of organomercury, organolead, andorganotin. J Toxicol Sci.1990;15Suppl4:125-151.
[10] Yoo CI, Kim Y, Jeong KS, Sim CS, Choy N, et al. A case of acute organotinpoisoning. J Occup Health.2007;49:305-310.
[11] Holloway LN, Pannell KH, Whalen MM Effects of a series of triorganotins on ATPlevels in human natural killer cells. Environ Toxicol Pharmacol.2008;25:43-50.
[12] Fortemps E, Amand G, Bomboir A, Lauwerys R, Laterre EC Trimethyltin poisoning.Report of two cases. Int Arch Occup Environ Health.1978;41:1-6.
[13] Ross WD, Emmett EA, Steiner J, Tureen R Neurotoxic effects of occupationalexposure to organotins. Am J Psychiatry.1981;138:1092-1095.
[14] Kreyberg S, Torvik A, Bjorneboe A, Wiik-Larsen W, Jacobsen D Trimethyltinpoisoning: report of a case with postmortem examination. Clin Neuropathol.1992;11:256-259.
[15] Ghosh BB, Talukder G, Sharma A Frequency of chromosome aberrations induced bytrimethyltin chloride in human peripheral blood lymphocytes in vitro: related to ageof donors. Mech Ageing Dev.1991;57:125-137.
[16] Gomez FD, Apodaca P, Holloway LN, Pannell KH, Whalen MM Effect of a seriesof triorganotins on the immune function of human natural killer cells. Environ ToxicolPharmacol.2007;23:18-24.
[17] Ohno H, Suzuki M, Nakashima S, Aoyama T, Mitani K [Determination of organotincompounds in plastic products by GC/MS after ethyl derivatization with sodiumtetraethylborate]. Shokuhin Eiseigaku Zasshi.2002;43:208-214.
[18] Fent K Ecotoxicology of organotin compounds. Crit Rev Toxicol.1996;26:1-117.
[19] Teuten EL, Saquing JM, Knappe DR, Barlaz MA, Jonsson S, et al. Transport andrelease of chemicals from plastics to the environment and to wildlife. Philos Trans RSoc Lond B Biol Sci.2009;364:2027-2045.
[20] Vajda FJ Neuroprotection and neurodegenerative disease. J Clin Neurosci.2002;9:4-8.
[21] Mattson MP Glutamate and neurotrophic factors in neuronal plasticity and disease.Ann N Y Acad Sci.2008;1144:97-112.
[22] Minghetti L Role of inflammation in neurodegenerative diseases. Curr Opin Neurol.2005;18:315-321.
[23] Parent JM Injury-induced neurogenesis in the adult mammalian brain.Neuroscientist.2003;9:261-272.
[24] Geloso MC, Corvino V, Michetti F Trimethyltin-induced hippocampal degenerationas a tool to investigate neurodegenerative processes. Neurochem Int.2011;58:729-738.
[25] Chang LW, Wenger GR, McMillan DE, Dyer RS Species and strain comparison ofacute neurotoxic effects of trimethyltin in mice and rats. Neurobehav Toxicol Teratol.1983;5:337-350.
[26] Harry GJ, Lefebvre d'Hellencourt C Dentate gyrus: alterations that occur withhippocampal injury. Neurotoxicology.2003;24:343-356.
[27] Misiti F, Orsini F, Clementi ME, Lattanzi W, Giardina B, et al. Mitochondrialoxygen consumption inhibition importance for TMT-dependent cell death inundifferentiated PC12cells. Neurochem Int.2008;52:1092-1099.
[28] Billingsley ML, Yun J, Reese BE, Davidson CE, Buck-Koehntop BA, et al.Functional and structural properties of stannin: roles in cellular growth, selectivetoxicity, and mitochondrial responses to injury. J Cell Biochem.2006;98:243-250.
[29] Piacentini R, Gangitano C, Ceccariglia S, Del Fa A, Azzena GB, et al.Dysregulation of intracellular calcium homeostasis is responsible for neuronal deathin an experimental model of selective hippocampal degeneration induced bytrimethyltin. J Neurochem.2008;105:2109-2121.
[30] Ceccariglia S, D'Altocolle A, Del Fa A, Pizzolante F, Caccia E, et al. Cathepsin Dplays a crucial role in the trimethyltin-induced hippocampal neurodegenerationprocess. Neuroscience.174:160-170.
[31] Casalbore P, Barone I, Felsani A, D'Agnano I, Michetti F, et al. Neural stem cellsmodified to express BDNF antagonize trimethyltin-induced neurotoxicity throughPI3K/Akt and MAP kinase pathways. J Cell Physiol.2010;224:710-721.
[32] Andersson H, Wetmore C, Lindqvist E, Luthman J, Olson L Trimethyltin exposurein the rat induces delayed changes in brain-derived neurotrophic factor, fos and heatshock protein70. Neurotoxicology.1997;18:147-159.
[33] Cohen-Cory S, Fraser SE Effects of brain-derived neurotrophic factor on optic axonbranching and remodelling in vivo. Nature.1995;378:192-196.
[34] McAllister AK, Lo DC, Katz LC Neurotrophins regulate dendritic growth indeveloping visual cortex. Neuron.1995;15:791-803.
[35] Ji Y, Lu Y, Yang F, Shen W, Tang TT, et al. Acute and gradual increases in BDNFconcentration elicit distinct signaling and functions in neurons. Nat Neurosci.2010;13:302-309.
[36] Tartaglia N, Du J, Tyler WJ, Neale E, Pozzo-Miller L, et al. Proteinsynthesis-dependent and-independent regulation of hippocampal synapses bybrain-derived neurotrophic factor. J Biol Chem.2001;276:37585-37593.
[37] Horch HW, Kruttgen A, Portbury SD, Katz LC Destabilization of cortical dendritesand spines by BDNF. Neuron.1999;23:353-364.
[38] Pozzo-Miller LD, Gottschalk W, Zhang L, McDermott K, Du J, et al. Impairmentsin high-frequency transmission, synaptic vesicle docking, and synaptic proteindistribution in the hippocampus of BDNF knockout mice. J Neurosci.1999;19:4972-4983.
[39] Otal R, Martinez A, Soriano E Lack of TrkB and TrkC signaling alters thesynaptogenesis and maturation of mossy fiber terminals in the hippocampus. CellTissue Res.2005;319:349-358.
[40] Aguado F, Carmona MA, Pozas E, Aguilo A, Martinez-Guijarro FJ, et al. BDNFregulates spontaneous correlated activity at early developmental stages by increasingsynaptogenesis and expression of the K+/Cl-co-transporter KCC2. Development.2003;130:1267-1280.
[41] Singh B, Henneberger C, Betances D, Arevalo MA, Rodriguez-Tebar A, et al.Altered balance of glutamatergic/GABAergic synaptic input and associated changesin dendrite morphology after BDNF expression in BDNF-deficient hippocampalneurons. J Neurosci.2006;26:7189-7200.
[42] Tanaka J, Horiike Y, Matsuzaki M, Miyazaki T, Ellis-Davies GC, et al. Proteinsynthesis and neurotrophin-dependent structural plasticity of single dendritic spines.Science.2008;319:1683-1687.
[43] Ma YL, Wang HL, Wu HC, Wei CL, Lee EH Brain-derived neurotrophic factorantisense oligonucleotide impairs memory retention and inhibits long-termpotentiation in rats. Neuroscience.1998;82:957-967.
[44] Alonso M, Vianna MR, Izquierdo I, Medina JH Signaling mechanisms mediatingBDNF modulation of memory formation in vivo in the hippocampus. Cell MolNeurobiol.2002;22:663-674.
[45] Nagahara AH, Tuszynski MH Potential therapeutic uses of BDNF in neurologicaland psychiatric disorders. Nat Rev Drug Discov.2011;10:209-219.
[46] Kemppainen S, Rantamaki T, Jeronimo-Santos A, Lavasseur G, Autio H, et al.Impaired TrkB receptor signaling contributes to memory impairment in APP/PS1mice. Neurobiol Aging.2012;33:1122e1123-1139.
[47] Nagahara AH, Merrill DA, Coppola G, Tsukada S, Schroeder BE, et al.Neuroprotective effects of brain-derived neurotrophic factor in rodent and primatemodels of Alzheimer's disease. Nat Med.2009;15:331-337.
[48] Kraft AD, McPherson CA, Harry GJ Heterogeneity of microglia and TNF signalingas determinants for neuronal death or survival. Neurotoxicology.2009;30:785-793.
[49] Tran HY, Shin EJ, Saito K, Nguyen XK, Chung YH, et al. Protective potential ofIL-6against trimethyltin-induced neurotoxicity in vivo. Free Radic Biol Med.2012;52:1159-1174.
[50] Jean Harry G, Bruccoleri A, Lefebvre d'Hellencourt C Differential modulation ofhippocampal chemical-induced injury response by ebselen, pentoxifylline, andTNFalpha-, IL-1alpha-, and IL-6-neutralizing antibodies. J Neurosci Res.2003;73:526-536.
[51] Brabeck C, Michetti F, Geloso MC, Corvino V, Goezalan F, et al. Expression ofEMAP-II by activated monocytes/microglial cells in different regions of the rathippocampus after trimethyltin-induced brain damage. Exp Neurol.2002;177:341-346.
[52] Little AR, Miller DB, Li S, Kashon ML, O'Callaghan JP Trimethyltin-inducedneurotoxicity: gene expression pathway analysis, q-RT-PCR and immunoblottingreveal early effects associated with hippocampal damage and gliosis. NeurotoxicolTeratol.2012;34:72-82.
[53] Liu Y, Imai H, Sadamatsu M, Tsunashima K, Kato N Cytokines participate inneuronal death induced by trimethyltin in the rat hippocampus via type IIglucocorticoid receptors. Neurosci Res.2005;51:319-327.
[54] Corvino V, Marchese E, Zarkovic N, Zarkovic K, Cindric M, et al. Distribution andtime-course of4-hydroxynonenal, heat shock protein110/105family members andcyclooxygenase-2expression in the hippocampus of rat during trimethyltin-inducedneurodegeneration. Neurochem Res.2011;36:1490-1500.
[55] Allaman I, Belanger M, Magistretti PJ Astrocyte-neuron metabolic relationships:for better and for worse. Trends Neurosci.2011;34:76-87.
[56] Zarkovic N, Zarkovic K, Schaur RJ, Stolc S, Schlag G, et al.4-Hydroxynonenal as asecond messenger of free radicals and growth modifying factor. Life Sci.1999;65:1901-1904.
[57] Coyle JT, Puttfarcken P Oxidative stress, glutamate, and neurodegenerativedisorders. Science.1993;262:689-695.
[58] Schulz JB, Lindenau J, Seyfried J, Dichgans J Glutathione, oxidative stress andneurodegeneration. Eur J Biochem.2000;267:4904-4911.
[59] Ali SF, LeBel CP, Bondy SC Reactive oxygen species formation as a biomarker ofmethylmercury and trimethyltin neurotoxicity. Neurotoxicology.1992;13:637-648.
[60] Shin EJ, Suh SK, Lim YK, Jhoo WK, Hjelle OP, et al. Ascorbate attenuatestrimethyltin-induced oxidative burden and neuronal degeneration in the rathippocampus by maintaining glutathione homeostasis. Neuroscience.2005;133:715-727.
[61] Haddad el B, McCluskie K, Birrell MA, Dabrowski D, Pecoraro M, et al.Differential effects of ebselen on neutrophil recruitment, chemokine, andinflammatory mediator expression in a rat model of lipopolysaccharide-inducedpulmonary inflammation. J Immunol.2002;169:974-982.
[62] Koizumi H, Fujisawa H, Suehiro E, Shirao S, Suzuki M Neuroprotective effects ofebselen following forebrain ischemia: involvement of glutamate and nitric oxide.Neurol Med Chir (Tokyo).2011;51:337-343.
[63] Block ML, Hong JS Microglia and inflammation-mediated neurodegeneration:multiple triggers with a common mechanism. Prog Neurobiol.2005;76:77-98.
[64] Straiko MM, Gudelsky GA, Coolen LM, Harrison R, Zemlan FP Treatment withtrimethyltin promotes the formation of cleaved tau in the rat brain. J Neurosci Res.2006;84:1116-1123.
[65] Farias G, Cornejo A, Jimenez J, Guzman L, Maccioni RB Mechanisms of tauself-aggregation and neurotoxicity. Curr Alzheimer Res.2011;8:608-614.
[66] Hanger DP, Anderton BH, Noble W Tau phosphorylation: the therapeutic challengefor neurodegenerative disease. Trends Mol Med.2009;15:112-119.
[67] Liu F, Li B, Tung EJ, Grundke-Iqbal I, Iqbal K, et al. Site-specific effects of tauphosphorylation on its microtubule assembly activity and self-aggregation. Eur JNeurosci.2007;26:3429-3436.
[68] Mondragon-Rodriguez S, Mena R, Binder LI, Smith MA, Perry G, et al.Conformational changes and cleavage of tau in Pick bodies parallel the earlyprocessing of tau found in Alzheimer pathology. Neuropathol Appl Neurobiol.2008;34:62-75.
[69] Mondragon-Rodriguez S, Trillaud-Doppia E, Dudilot A, Bourgeois C, Lauzon M, et al.Interaction of endogenous tau protein with synaptic proteins is regulated byN-methyl-D-aspartate receptor-dependent tau phosphorylation. J Biol Chem.2012;287:32040-32053.
[70] Ho YS, Yang X, Lau JC, Hung CH, Wuwongse S, et al. Endoplasmic reticulumstress induces tau pathology and forms a vicious cycle: implication in Alzheimer'sdisease pathogenesis. J Alzheimers Dis.2012;28:839-854.
[71] Kim SU, de Vellis J Stem cell-based cell therapy in neurological diseases: a review.J Neurosci Res.2009;87:2183-2200.
[72] Woodruff ML, Baisden RH, Nonneman AJ Anatomical and behavioral sequelae offetal brain transplants in rats with trimethyltin-induced neurodegeneration.Neurotoxicology.1991;12:427-444.
[73] Roy A, Agrawal AK, Husain R, Dubey MP, Seth PK Cholinergic and serotonergicalterations in the rat hippocampus following trimethyltin exposure and fetal neuraltransplantation. Neurosci Lett.1999;259:173-176.
[74] Yoneyama M, Seko K, Kawada K, Sugiyama C, Ogita K High susceptibility ofcortical neural progenitor cells to trimethyltin toxicity: involvement of both caspasesand calpain in cell death. Neurochem Int.2009;55:257-264.
[75] Martino G, Pluchino S, Bonfanti L, Schwartz M Brain regeneration in physiologyand pathology: the immune signature driving therapeutic plasticity of neural stemcells. Physiol Rev.2011;91:1281-1304.
[76] Corvino V, Geloso MC, Cavallo V, Guadagni E, Passalacqua R, et al. Enhancedneurogenesis during trimethyltin-induced neurodegeneration in the hippocampus ofthe adult rat. Brain Res Bull.2005;65:471-477.
[77] McPherson CA, Aoyama M, Harry GJ Interleukin (IL)-1and IL-6regulation ofneural progenitor cell proliferation with hippocampal injury: differential regulatorypathways in the subgranular zone (SGZ) of the adolescent and mature mouse brain.Brain Behav Immun.2011;25:850-862.
[78] Gray WP Neuropeptide Y signalling on hippocampal stem cells in health anddisease. Mol Cell Endocrinol.2008;288:52-62.
[79] Corvino V, Marchese E, Giannetti S, Lattanzi W, Bonvissuto D, et al. Theneuroprotective and neurogenic effects of neuropeptide Y administration in an animalmodel of hippocampal neurodegeneration and temporal lobe epilepsy induced bytrimethyltin. J Neurochem.2012;122:415-426.