ICAM-5通过ERM/PI3K/Akt信号途径减轻Aβ诱导的神经变性
|
摘要
研究背景阿尔茨海默病(Alzheimer's disease,AD)的典型神经病理特征是患者脑内出现以β-淀粉样蛋白(amyloid beta peptide,Aβ)为主要成分的神经元外老年斑(senile plaque,SP)、神经元内神经原纤维缠结(neurofibrillary tangles,NFTs)、广泛的神经元变性消失。神经元变性凋亡涉及信号转导、基因调控和凋亡效应等三个阶段。信号转导过程的激活是启动细胞变性凋亡的必要前提,从而调控细胞存活与死亡。神经元变性凋亡的发生机制主要涉及两条信号转导通路,即线粒体通路和膜死亡受体通路。二者最后都启动caspase的级联反应而引起神经元凋亡。此外,细胞周期异常也可以影响到神经元的存活。神经元内外存在着在各种致凋亡因素,同时也存在着抗凋亡的相关信号途径,其中经典的抗凋亡信号途径是磷脂酰肌醇-3激酶(phosphoinositide-3kinase,P13K)/丝氨酸-苏氨酸蛋白激酶(Akt)信号通路。
细胞间黏附分子5(Intercellular adhesion molecule-5,ICAM-5,telencephalin)是一种在哺育动物端脑神经元体树突膜特异性表达的复杂黏附分子,具有促进神经元树突生长与影响学习记忆功能的作用。ICAM-5的胞质区结合于埃兹蛋白-根蛋白-膜突蛋白(ezrin-radixin-moesin,ERM)家族蛋白使膜蛋白与细胞骨架肌动蛋白连接起来,而ERM的磷酸化活性形式可以启动PI3K/Akt信号通路。因此,ICAM-5可能通过激活ERM蛋白而启动PI3K/Akt信号通路。但其是否可以对抗Aβ的神经毒性或参与信号传导,目前国内外无这方面的报道。
研究目的探索ICAM-5是否减轻或缓解Aβ的神经毒性作用和激活抗凋亡的PI3K/Akt信号通路来阻断Aβ诱导的凋亡信号传导,为AD和其他神经变性疾病的防治提供相关基础。
研究方法1.建立神经元模型:用常表达人野生型ICAM-5蛋白的人神经母细胞瘤细胞PAJU-ICAM-5进行连续不加压传代,使其质粒脱失,经免疫荧光和Western Blot鉴定为PAJU细胞后转染含NEO抗性基因的空载体,建立空载体转染的对照细胞模型PAJU-NEO;2.用Aβ作为神经毒性刺激物,分别对PAJU-ICAM-5和PAJU-NEO细胞进行不同浓度和时间段刺激,采用MTT法检测神经元活力、Hoechst 33258神经元核染色观察核凋亡、流式细胞仪检测神经元凋亡,以了解ICAM-5是否具有保护神经元对抗Aβ的整体作用;同时用蛋白免疫印迹技术检测Aβ对ICAM-5表达的影响;3.测量在不同浓度和时间段Aβ作用下的神经突起,并使用免疫荧光染色,观察Aβ对神经突起末梢的影响,以了解CAM-5表达是否具有保护神经突起对Aβ的局部作用;4.采用免疫印迹技术检测Aβ刺激作用后磷酸化蛋白的表达,以了解抗凋亡变性信号途径是否被激活。
研究结果1.PAJU-ICAM-5细胞经不加压连续传代10代后出现质粒完全脱失,经过免疫荧光检测和Western Blot验证无ICAM-5表达;空载体pcDNA3.1转染的PAJU-NEO细胞株建立。2.ICAM-5蛋白常量稳定表达于PAJU细胞后,可减轻Aβ诱导的PAJU细胞凋亡变性,表现为细胞存活率升高和凋亡率降低。同时,表达于PAJU细胞中的ICAM-5蛋白在经受长时间高浓度Aβ42作用后出现降低趋势。3.PAJU-ICAM-5细胞突起分支长度损伤较PAJU-NEO细胞明显减轻。4.通过免疫印记技术发现,ICAM-5蛋白的表达使Moesin蛋白的558位苏氨酸(Thr558)残基磷酸化而形成活化状态,经Aβ刺激后引起其家族蛋白中的Ezrin蛋白的第567位苏氨残基酸(Thr567)和Radixin蛋白的564位苏氨酸(Thr564)出现磷酸化激活,并由此导致了PI3K蛋白调节亚单位p85α的508位酪氨酸残基(Tyr508,p85α)磷酸化,引起PI3K活化,PI3K直接促使Akt蛋白的473位丝氨酸(Ser-473)残基磷酸化而激活了信号通路。5.PI3K特异性抑制剂LY294002不仅下调PI3K蛋白表达,而且还可以下调ICAM-5、磷酸化ERM、磷酸化PI3K及磷酸化Akt蛋白的表达,而总ERM、总PI3K及总Akt却表达于未经LY294002和Aβ处理以及经过LY294002和Aβ处理过的PAJU细胞。提示LY294002可能是这条信号通路上的生物学调节标志。
研究结论1.我们首次证明了ICAM-5蛋白常表达具有神经保护作用,可以减轻Aβ神经毒性所致的PAJU细胞凋亡及神经突起变性。2.Aβ42与ICAM-5之间具有相互作用,长时间高剂量的Aβ42使ICAM-5表达下调。3.首次发现ICAM-5通过激活ERM而激活PI3K/Akt信号途径,因此减轻Aβ诱导的神经变性。4.LY294002可能是ERM/PI3K/Akt信号通路上的生物学调节点。
Backgroud Alzheimer's disease(AD) is a neurodegenerative disorder pathologically by accumulation of amyloid beta protein(Aβ),a major constituent of extracellular senile plaque(SP) and intracellular neurofibrillary tangles(NFTs) and loss of cholinergic neurons.Neuronal degeneration and apoptosis are involved in three stage including signal transduction,gene regulation and apoptosis execution.Activation of signal transduction procedure is the essential condition of initiating neuron apoptosis and regulates cell survival and death.The mechanism of neuronal degeneration or apoptosis includes two major cell death signaling pathways which are mitochondrial death pathway and death receptor pathway.The two pathways start caspase cascade reaction at last and lead neurons death. Besides,abnormal of cell cycle also affects neuron survival.In the process of neurons apoptosis,there also exist relative anti-apoptosis signaling pathways.The typical one is phosphatidylinositol 3-kinase(PI3K)/Akt pathway.
Intercellular adhesion molecule-5(ICAM-5,telencephalin) is a cell adhesion molecule expressed in the somatodendritic membrane of telencephalic neurons in mammalian brain.It induces dendritic outgrowth and is involved in regulation of memory formation and learning.ICAM-5 cytoplasmic region binds ERM(ezrin/radixin/moesin) family proteins that link membrane proteins to actin cytoskeleton.And phosphorylation of ERM can initiate PI3K/Akt pathway.But there is no research on whether ICAM-5 can abate Aβneurotoxicity or is involved in signaling transduction.
Objective To explor whether ICAM-5 can abate neurotoxicity of Aβand initiate PI3K/Akt pathway,and provide relative basis for prevention and cure of AD and other neurodegenerative diseases.
Methods 1.The control neuronal model PAJU-NEO was established by transfected PAJU cells with empty vector pcDNA3.1.And PAJU cells were obtained by successive passage of PAJU-ICAM-5 without pressure selection.It was identified by immunofluorescence and western blotting.2. We treated PAJU-ICAM-5 and PAJU-NEO cells with different concentrations of Aβin different times.To detect neuronal survival rate with MTT and apoptosis rate with Hoechst 33258 and flow cytometry. Western blotting was used to find out effect of Aβon expression of ICAM-5.3.To measuer process of PAJU-ICAM-5 and PAJU-NEO cells cultured in different concentrations of Aβin different times.And immunofluorescence was used to observe neurites damage.4.Western blotting was used to find out phosphorylation of Ezrin(Thr567),Radixin (Thr564) and Moesin(Thr558),PI3K(Tyr508,p85α) and Akt(Ser473).
Results 1.Neuronal model PAJU-NEO was established and express neo resistivity.2.We discovered that nomalexpression of ICAM-5 can protect neurons from Aβneurotoxicity(Aβ_(42) 1.0nmol/L) induced apoptosis, as indicated by increase neuronal survival rate and decrease damage of neurites(Aβ_(42) and Aβ_(35) 0.5,0.8nmol/L) and apoptosis rate.Meanwhile, ICAM-5 expression down regulation present due to long time expose to Aβ. 3.Furthermore,ICAM-5 interacted with ezrin-radixin-moesin(ERM) protein family in PAJU cells,and active phosphorylation of Ezrin(Thr567), Radixin(Thr564) and Moesin(Thr558).Phosphorylated ERM activated phosphorylation of PI3K(TyrS08,p85α),which made activation of Akt (Ser473) directly.4.Western blot analysis showed that 30μM of the LY294002 markedly inhibited ICAM-5,phospho-ERM,phospho-PI3K and phospho-Akt in PAJU cells,while the total ERM,PI3K and Akt expression in both PAJU-ICAM-5 and PAJU-NEO cell lines was identical in nontreated and treated cells.It suggested that LY294002 play a role on this pathway in the biological regulation of this marker.
Conclusion 1.Here we demonstrate for the first time that nomalexpression of ICAM-5 in human neuroblastoma PAJU cells can protect the neurons from Aβneurotoxicity as indicated by reduce apoptosis and neurites degeneration,increase neuronal survival rate.2.Long time expose to Aβmay reduce expression level of ICAM-5.3.We also demonstrate for the first time that ICAM-5 attenuates amyloid beta protein induced neuronal degeneration by ERM/PI3K/Akt pathway.4.LY294002 may be a biological regulative marker of ERM/PI3K/Akt pathway.
细胞间黏附分子5(Intercellular adhesion molecule-5,ICAM-5,telencephalin)是一种在哺育动物端脑神经元体树突膜特异性表达的复杂黏附分子,具有促进神经元树突生长与影响学习记忆功能的作用。ICAM-5的胞质区结合于埃兹蛋白-根蛋白-膜突蛋白(ezrin-radixin-moesin,ERM)家族蛋白使膜蛋白与细胞骨架肌动蛋白连接起来,而ERM的磷酸化活性形式可以启动PI3K/Akt信号通路。因此,ICAM-5可能通过激活ERM蛋白而启动PI3K/Akt信号通路。但其是否可以对抗Aβ的神经毒性或参与信号传导,目前国内外无这方面的报道。
研究目的探索ICAM-5是否减轻或缓解Aβ的神经毒性作用和激活抗凋亡的PI3K/Akt信号通路来阻断Aβ诱导的凋亡信号传导,为AD和其他神经变性疾病的防治提供相关基础。
研究方法1.建立神经元模型:用常表达人野生型ICAM-5蛋白的人神经母细胞瘤细胞PAJU-ICAM-5进行连续不加压传代,使其质粒脱失,经免疫荧光和Western Blot鉴定为PAJU细胞后转染含NEO抗性基因的空载体,建立空载体转染的对照细胞模型PAJU-NEO;2.用Aβ作为神经毒性刺激物,分别对PAJU-ICAM-5和PAJU-NEO细胞进行不同浓度和时间段刺激,采用MTT法检测神经元活力、Hoechst 33258神经元核染色观察核凋亡、流式细胞仪检测神经元凋亡,以了解ICAM-5是否具有保护神经元对抗Aβ的整体作用;同时用蛋白免疫印迹技术检测Aβ对ICAM-5表达的影响;3.测量在不同浓度和时间段Aβ作用下的神经突起,并使用免疫荧光染色,观察Aβ对神经突起末梢的影响,以了解CAM-5表达是否具有保护神经突起对Aβ的局部作用;4.采用免疫印迹技术检测Aβ刺激作用后磷酸化蛋白的表达,以了解抗凋亡变性信号途径是否被激活。
研究结果1.PAJU-ICAM-5细胞经不加压连续传代10代后出现质粒完全脱失,经过免疫荧光检测和Western Blot验证无ICAM-5表达;空载体pcDNA3.1转染的PAJU-NEO细胞株建立。2.ICAM-5蛋白常量稳定表达于PAJU细胞后,可减轻Aβ诱导的PAJU细胞凋亡变性,表现为细胞存活率升高和凋亡率降低。同时,表达于PAJU细胞中的ICAM-5蛋白在经受长时间高浓度Aβ42作用后出现降低趋势。3.PAJU-ICAM-5细胞突起分支长度损伤较PAJU-NEO细胞明显减轻。4.通过免疫印记技术发现,ICAM-5蛋白的表达使Moesin蛋白的558位苏氨酸(Thr558)残基磷酸化而形成活化状态,经Aβ刺激后引起其家族蛋白中的Ezrin蛋白的第567位苏氨残基酸(Thr567)和Radixin蛋白的564位苏氨酸(Thr564)出现磷酸化激活,并由此导致了PI3K蛋白调节亚单位p85α的508位酪氨酸残基(Tyr508,p85α)磷酸化,引起PI3K活化,PI3K直接促使Akt蛋白的473位丝氨酸(Ser-473)残基磷酸化而激活了信号通路。5.PI3K特异性抑制剂LY294002不仅下调PI3K蛋白表达,而且还可以下调ICAM-5、磷酸化ERM、磷酸化PI3K及磷酸化Akt蛋白的表达,而总ERM、总PI3K及总Akt却表达于未经LY294002和Aβ处理以及经过LY294002和Aβ处理过的PAJU细胞。提示LY294002可能是这条信号通路上的生物学调节标志。
研究结论1.我们首次证明了ICAM-5蛋白常表达具有神经保护作用,可以减轻Aβ神经毒性所致的PAJU细胞凋亡及神经突起变性。2.Aβ42与ICAM-5之间具有相互作用,长时间高剂量的Aβ42使ICAM-5表达下调。3.首次发现ICAM-5通过激活ERM而激活PI3K/Akt信号途径,因此减轻Aβ诱导的神经变性。4.LY294002可能是ERM/PI3K/Akt信号通路上的生物学调节点。
Backgroud Alzheimer's disease(AD) is a neurodegenerative disorder pathologically by accumulation of amyloid beta protein(Aβ),a major constituent of extracellular senile plaque(SP) and intracellular neurofibrillary tangles(NFTs) and loss of cholinergic neurons.Neuronal degeneration and apoptosis are involved in three stage including signal transduction,gene regulation and apoptosis execution.Activation of signal transduction procedure is the essential condition of initiating neuron apoptosis and regulates cell survival and death.The mechanism of neuronal degeneration or apoptosis includes two major cell death signaling pathways which are mitochondrial death pathway and death receptor pathway.The two pathways start caspase cascade reaction at last and lead neurons death. Besides,abnormal of cell cycle also affects neuron survival.In the process of neurons apoptosis,there also exist relative anti-apoptosis signaling pathways.The typical one is phosphatidylinositol 3-kinase(PI3K)/Akt pathway.
Intercellular adhesion molecule-5(ICAM-5,telencephalin) is a cell adhesion molecule expressed in the somatodendritic membrane of telencephalic neurons in mammalian brain.It induces dendritic outgrowth and is involved in regulation of memory formation and learning.ICAM-5 cytoplasmic region binds ERM(ezrin/radixin/moesin) family proteins that link membrane proteins to actin cytoskeleton.And phosphorylation of ERM can initiate PI3K/Akt pathway.But there is no research on whether ICAM-5 can abate Aβneurotoxicity or is involved in signaling transduction.
Objective To explor whether ICAM-5 can abate neurotoxicity of Aβand initiate PI3K/Akt pathway,and provide relative basis for prevention and cure of AD and other neurodegenerative diseases.
Methods 1.The control neuronal model PAJU-NEO was established by transfected PAJU cells with empty vector pcDNA3.1.And PAJU cells were obtained by successive passage of PAJU-ICAM-5 without pressure selection.It was identified by immunofluorescence and western blotting.2. We treated PAJU-ICAM-5 and PAJU-NEO cells with different concentrations of Aβin different times.To detect neuronal survival rate with MTT and apoptosis rate with Hoechst 33258 and flow cytometry. Western blotting was used to find out effect of Aβon expression of ICAM-5.3.To measuer process of PAJU-ICAM-5 and PAJU-NEO cells cultured in different concentrations of Aβin different times.And immunofluorescence was used to observe neurites damage.4.Western blotting was used to find out phosphorylation of Ezrin(Thr567),Radixin (Thr564) and Moesin(Thr558),PI3K(Tyr508,p85α) and Akt(Ser473).
Results 1.Neuronal model PAJU-NEO was established and express neo resistivity.2.We discovered that nomalexpression of ICAM-5 can protect neurons from Aβneurotoxicity(Aβ_(42) 1.0nmol/L) induced apoptosis, as indicated by increase neuronal survival rate and decrease damage of neurites(Aβ_(42) and Aβ_(35) 0.5,0.8nmol/L) and apoptosis rate.Meanwhile, ICAM-5 expression down regulation present due to long time expose to Aβ. 3.Furthermore,ICAM-5 interacted with ezrin-radixin-moesin(ERM) protein family in PAJU cells,and active phosphorylation of Ezrin(Thr567), Radixin(Thr564) and Moesin(Thr558).Phosphorylated ERM activated phosphorylation of PI3K(TyrS08,p85α),which made activation of Akt (Ser473) directly.4.Western blot analysis showed that 30μM of the LY294002 markedly inhibited ICAM-5,phospho-ERM,phospho-PI3K and phospho-Akt in PAJU cells,while the total ERM,PI3K and Akt expression in both PAJU-ICAM-5 and PAJU-NEO cell lines was identical in nontreated and treated cells.It suggested that LY294002 play a role on this pathway in the biological regulation of this marker.
Conclusion 1.Here we demonstrate for the first time that nomalexpression of ICAM-5 in human neuroblastoma PAJU cells can protect the neurons from Aβneurotoxicity as indicated by reduce apoptosis and neurites degeneration,increase neuronal survival rate.2.Long time expose to Aβmay reduce expression level of ICAM-5.3.We also demonstrate for the first time that ICAM-5 attenuates amyloid beta protein induced neuronal degeneration by ERM/PI3K/Akt pathway.4.LY294002 may be a biological regulative marker of ERM/PI3K/Akt pathway.
引文
[1]Ewbank DC.Deaths attributable to Alzheimer's disease in the United States.Am J Public Health.1999;89(1):90-92.
[2]盛树力.老年性痴呆及相关疾病.北京:科学技术文献出版社,2006.
[3]Hardy JA,Higgins GA.Alzheimer's disease:the amyloid cascade hypothesis.Science.1992;256(5054):184-185.
[4]Lambert MP,Barlow AK,Chromy BA,Edwards C,Freed R,Liosatos M,Morgan TE,Rozovsky I,Trommer B,Viola KL,Wals P,Zhang C,Finch CE,Krafft GA,Klein WL.Diffusible,nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins.Proc Natl Acad Sci U S A.1998;95(11):6448-6453.
[5]Walsh DM,Klyubin I,Fadeeva JV,Cullen WK,Anwyl R,Wolfe MS,Rowan MJ,Selkoe DJ.Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.Nature.2002;416(6880):535-539.
[6]Walsh DM,Townsend M,Podlisny MB,Shankar GM,Fadeeva JV,El Agnaf O,Hartley DM,Selkoe DJ.Certain inhibitors of synthetic amyloid beta-peptide(Abeta)fibrillogenesis block oligomerization of natural Abeta and thereby rescue long-term potentiation.J Neurosci.2005;25(10):2455-2462.
[7]Ye C,Walsh DM,Selkoe DJ,Hartley DM.Amyloid beta-protein induced electrophysiological changes are dependent on aggregation state:N-methyl-D-aspartate (NMDA) versus non-NMDA receptor/channel activation.Neurosci Lett.2004;366(3):320-325.
[8]Matharu B,Gibson G,Parsons R,Huckerby TN,Moore SA,Cooper LJ,Millichamp R,Allsop D,Austen B.Galantamine inhibits beta-amyloid aggregation and cytotoxicity.J Neurol Sci.2009.
[9]Glenner GG,Wong CW.Alzheimer's disease:initial report of the purification and characterization of a novel cerebrovascular amyloid protein.Biochem Biophys Res Commun.1984;120(3):885-890.
[10]Yankner BA,Dawes LR,Fisher S,Villa-Komaroff L,Oster-Granite ML,Neve RL. Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease. Science. 1989;245(4916):417-420.
[11] Frautschy SA, Baird A, Cole GM. Effects of injected Alzheimer beta-amyloid cores in rat brain. Proc Natl Acad Sci U S A. 1991;88(19):8362-8366.
[12] Pike CJ, Walencewicz AJ, Glabe CG, Cotman CW. In vitro aging of beta-amyloid protein causes peptide aggregation and neurotoxicity. Brain Res.1991;563(1-2):311-314.
[13] Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M,Ashe KH. A specific amyloid-beta protein assembly in the brain impairs memory.Nature. 2006;440(7082):352-357.
[14] Smale G, Nichols NR, Brady DR, Finch CE, Horton WE, Jr. Evidence for apoptotic cell death in Alzheimer's disease. Exp Neurol. 1995;133(2):225-230.
[15] Golde TE. Alzheimer disease therapy: can the amyloid cascade be halted? J Clin Invest.2003;111(1):11-18.
[16] Wu S, Zhou L, Rose M, Xiao X, Graham SH. c-FLIP-L recombinant adeno-associated virus vector infection prevents Fas-mediated but not nerve growth factor withdrawal-mediated cell death in PC12 cells. Brain Res Mol Brain Res.2004;122(1):79-87.
[17] Su JH, Anderson AJ, Cribbs DH, Tu C, Tong L, Kesslack P, Cotman CW. Fas and Fas ligand are associated with neuritic degeneration in the AD brain and participate in beta-amyloid-induced neuronal death. Neurobiol Dis. 2003; 12(3): 182-193.
[18] Vincent I, Rosado M, Davies P. Mitotic mechanisms in Alzheimer's disease? J Cell Biol. 1996;132(3):413-425.
[19] Vincent I, Jicha G, Rosado M, Dickson DW. Aberrant expression of mitotic cdc2/cyclin B1 kinase in degenerating neurons of Alzheimer's disease brain. J Neurosci.1997;17(10):3588-3598.
[20] McShea A, Harris PL, Webster KR, Wahl AF, Smith MA. Abnormal expression of the cell cycle regulators P16 and CDK4 in Alzheimer's disease. Am J Pathol. 1997; 150(6): 1933-1939.
[21] Neve RL, McPhie DL. Dysfunction of amyloid precursor protein signaling in neurons leads to DNA synthesis and apoptosis. Biochim Biophys Acta.2007;1772(4):430-437.
[22] Nagy Z. The dysregulation of the cell cycle and the diagnosis of Alzheimer's disease. Biochim Biophys Acta. 2007;1772(4):402-408.
[23] Meda L, Bernasconi S, Bonaiuto C, Sozzani S, Zhou D, Otvos L, Jr.,Mantovani A, Rossi F, Cassatella MA. Beta-amyloid (25-35) peptide and IFN-gamma synergistically induce the production of the chemotactic cytokine MCP-l/JE in monocytes and microglial cells. J Immunol. 1996;157(3):1213-1218.
[24] Behl C, Davis JB, Lesley R, Schubert D. Hydrogen peroxide mediates amyloid beta protein toxicity. Cell. 1994;77(6):817-827.
[25] Butterfield DA, Hensley K, Harris M, Mattson M, Carney J. beta-Amyloid peptide free radical fragments initiate synaptosomal lipoperoxidation in a sequence-specific fashion: implications to Alzheimer's disease. Biochem Biophys Res Commun. 1994;200(2):710-715.
[26] Cafe C, Torri C, Bertorelli L, Angeretti N, Lucca E, Forloni G, Marzatico F.Oxidative stress after acute and chronic application of beta-amyloid fragment 25-35 in cortical cultures. Neurosci Lett. 1996;203(1):61-65.
[27] Casley CS, Land JM, Sharpe MA, Clark JB, Duchen MR, Canevari L.Beta-amyloid fragment 25-35 causes mitochondrial dysfunction in primary cortical neurons. Neurobiol Dis. 2002;10(3):258-267.
[28] Blass JP. Brain metabolism and brain disease: is metabolic deficiency the proximate cause of Alzheimer dementia? J Neurosci Res. 2001;66(5):851-856.
[29] Yuan J, Yankner BA. Apoptosis in the nervous system. Nature.2000;407(6805):802-809.
[30] Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, Yuan J.Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature. 2000;403(6765):98-103.
[31] Jellinger KA. Cell death mechanisms in neurodegeneration. J Cell Mol Med.2001;5(1):1-17.
[32] Jin Z, El-Deiry WS. Overview of cell death signaling pathways. Cancer Biol Ther.2005;4(2):139-163.
[33] Stefanis L. Caspase-dependent and -independent neuronal death: two distinct pathways to neuronal injury. Neuroscientist. 2005;11(1):50-62.
[34] Huang DC, Strasser A. BH3-Only proteins-essential initiators of apoptotic cell death. Cell. 2000;103(6):839-842.
[35] van Delft MF, Huang DC. How the Bcl-2 family of proteins interact to regulate apoptosis. Cell Res. 2006;16(2):203-213.
[36] Willis SN, Adams JM. Life in the balance: how BH3-only proteins induce apoptosis. Curr Opin Cell Biol. 2005;17(6):617-625.
[37] Puthalakath H, Strasser A. Keeping killers on a tight leash: transcriptional and post-translational control of the pro-apoptotic activity of BH3-only proteins. Cell Death Differ. 2002;9(5):505-512.
[38] Bouillet P, Strasser A. BH3-only proteins - evolutionarily conserved proapoptotic Bcl-2 family members essential for initiating programmed cell death. J Cell Sci. 2002;115(Pt 8):1567-1574.
[39] Precht TA, Phelps RA, Linseman DA, Butts BD, Le SS, Laessig TA, Bouchard RJ, Heidenreich KA. The permeability transition pore triggers Bax translocation to mitochondria during neuronal apoptosis. Cell Death Differ. 2005;12(3):255-265.
[40] Fujimura M, Morita-Fujimura Y, Murakami K, Kawase M, Chan PH. Cytosolic redistribution of cytochrome c after transient focal cerebral ischemia in rats. J Cereb Blood Flow Metab. 1998;18(11):1239-1247.
[41] Janicke RU, Sprengart ML, Wati MR, Porter AG. Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J Biol Chem. 1998;273(16):9357-9360.
[42] Shi Y. Caspase activation, inhibition, and reactivation: a mechanistic view.Protein Sci. 2004;13(8):1979-1987.
[43] Gastard MC, Troncoso JC, Koliatsos VE. Caspase activation in the limbic cortex of subjects with early Alzheimer's disease. Ann Neurol. 2003;54(3):393-398.
[44] Bhat RV, Leonov S, Luthman J, Scott CW, Lee CM. Interactions between GSK3beta and caspase signalling pathways during NGF deprivation induced cell death. J Alzheimers Dis. 2002;4(4):291-301.
[45] Jover T, Tanaka H, Calderone A, Oguro K, Bennett MV, Etgen AM, Zukin RS.Estrogen protects against global ischemia-induced neuronal death and prevents activation of apoptotic signaling cascades in the hippocampal CA1. J Neurosci.2002;22(6):2115-2124.
[46] Nagata S. Fas ligand-induced apoptosis. Annu Rev Genet. 1999;33:29-55.
[47] Mogi M, Harada M, Kondo T, Mizuno Y, Narabayashi H, Riederer P, Nagatsu T. The soluble form of Fas molecule is elevated in parkinsonian brain tissues. Neurosci Lett. 1996;220(3):195-198.
[48] Paschen W. Role of calcium in neuronal cell injury: which subcellular compartment is involved? Brain Res Bull. 2000;53(4):409-413.
[49] Shimoke K, Amano H, Kishi S, Uchida H, Kudo M, Ikeuchi T. Nerve growth factor attenuates endoplasmic reticulum stress-mediated apoptosis via suppression of caspase-12 activity. J Biochem. 2004;135(3):439-446.
[50] Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH.Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration.Nature. 1999;402(6762):615-622.
[51] Lim AC, Qi RZ. Cyclin-dependent kinases in neural development and degeneration. J Alzheimers Dis. 2003;5(4):329-335.
[52] Nguyen MD, Mushynski WE, Julien JP. Cycling at the interface between neurodevelopment and neurodegeneration. Cell Death Differ. 2002;9(12):1294-1306.
[53] Lopes JP, Oliveira CR, Agostinho P. Role of cyclin-dependent kinase 5 in the neurodegenerative process triggered by amyloid-Beta and prion peptides: implications for Alzheimer's disease and prion-related encephalopathies. Cell Mol Neurobiol.2007;27(7):943-957.
[54] Walsh FS, Doherty P. Neural cell adhesion molecules of the immunoglobulin superfamily: role in axon growth and guidance. Annu Rev Cell Dev Biol.1997;13:425-456.
[55] Shapiro L, Colman DR. The diversity of cadherins and implications for a synaptic adhesive code in the CNS. Neuron. 1999;23(3):427-430.
[56] Hynes RO, Lander AD. Contact and adhesive specificities in the associations,migrations, and targeting of cells and axons. Cell. 1992;68(2):303-322.
[57] Goodman CS, Shatz CJ. Developmental mechanisms that generate precise patterns of neuronal connectivity. Cell. 1993;72 Suppl:77-98.
[58] Yoshihara Y, Mori K. Telencephalin: a neuronal area code molecule? Neurosci Res. 1994;21(2):119-124.
[59] Brummendorf T, Rathjen FG. Structure/function relationships of axon-associated adhesion receptors of the immunoglobulin superfamily. Curr Opin Neurobiol. 1996;6(5):584-593.
[60] Sonderegger P, Rathjen FG. Regulation of axonal growth in the vertebrate nervous system by interactions between glycoproteins belonging to two subgroups of the immunoglobulin superfamily. J Cell Biol. 1992;119(6):1387-1394.
[61] Larson RS, Springer TA. Structure and function of leukocyte integrins.Immunol Rev. 1990;114:181-217.
[62] Gahmberg CG. Leukocyte adhesion: CD11/CD18 integrins and intercellular adhesion molecules. Curr Opin Cell Biol. 1997;9(5):643-650.
[63] Gahmberg CG, Tolvanen M, Kotovuori P. Leukocyte adhesion—structure and function of human leukocyte beta2-integrins and their cellular ligands. Eur J Biochem.1997;245(2):215-232.
[64] Yoshihara Y, Oka S, Nemoto Y, Watanabe Y, Nagata S, Kagamiyama H, Mori K. An ICAM-related neuronal glycoprotein, telencephalin, with brain segment-specific expression. Neuron. 1994;12(3):541-553.
[65] Mizuno T, Yoshihara Y, Inazawa J, Kagamiyama H, Mori K. cDNA cloning and chromosomal localization of the human telencephalin and its distinctive interaction with lymphocyte function-associated antigen-1. J Biol Chem. 1997;272(2):1156-1163.
[66] Hayflick JS, Kilgannon P, Gallatin WM. The intercellular adhesion molecule (ICAM) family of proteins. New members and novel functions. Immunol Res.1998;17(3):313-327.
[67] Gahmberg CG, Tian L, Ning L, Nyman-Huttunen H. ICAM-5--a novel two-facetted adhesion molecule in the mammalian brain. Immunol Lett. 2008;117(2):131-135.
[68] Hino H, Mori K, Yoshihara Y, Iseki E, Akiyama H, Nishimura T, Ikeda K,Kosaka K. Reduction of telencephalin immunoreactivity in the brain of patients with Alzheimer's disease. Brain Res. 1997;753(2):353-357.
[69] Rieckmann P, Turner T, Kligannon P, Steinhoff BJ. Telencephalin as an indicator for temporal-lobe dysfunction. Lancet. 1998;352(9125):370-371.
[70] Furutani Y, Matsuno H, Kawasaki M, Sasaki T, Mori K, Yoshihara Y.Interaction between telencephalin and ERM family proteins mediates dendritic filopodia formation. J Neurosci. 2007;27(33):8866-8876.
[71] Gautreau A, Poullet P, Louvard D, Arpin M. Ezrin, a plasma membrane-microfilament linker, signals cell survival through the phosphatidylinositol 3-kinase/Akt pathway. Proc Natl Acad Sci U S A. 1999;96(13):7300-7305.
[72] Mori K, Fujita SC, Watanabe Y, Obata K, Hayaishi O. Telencephalon-specific antigen identified by monoclonal antibody. Proc Natl Acad Sci U S A.1987;84(11):3921-3925.
[73] Oka S, Mori K, Watanabe Y. Mammalian telencephalic neurons express a segment-specific membrane glycoprotein, telencephalin. Neuroscience.1990;35(1):93-103.
[74] Trask B, Fertitta A, Christensen M, Youngblom J, Bergmann A, Copeland A,de Jong P, Mohrenweiser H, Olsen A, Carrano A, et al. Fluorescence in situ hybridization mapping of human chromosome 19: cytogenetic band location of 540 cosmids and 70 genes or DNA markers. Genomics. 1993;15(1):133-145.
[75] Kilgannon P, Turner T, Meyer J, Wisdom W, Gallatin WM. Mapping of the ICAM-5 (telencephalin) gene, a neuronal member of the ICAM family, to a location between ICAM-1 and ICAM-3 on human chromosome 19p13.2. Genomics.1998;54(2):328-330.
[76] Tian L, Yoshihara Y, Mizuno T, Mori K, Gahmberg CG. The neuronal glycoprotein telencephalin is a cellular ligand for the CD1 la/CD 18 leukocyte integrin. J Immunol. 1997;158(2):928-936.
[77] Tian L, Kilgannon P, Yoshihara Y, Mori K, Gallatin WM, Carpen O, Gahmberg CG. Binding of T lymphocytes to hippocampal neurons through ICAM-5 (telencephalin) and characterization of its interaction with the leukocyte integrin CDlla/CD18. Eur J Immunol. 2000;30(3):810-818.
[78] Murakami F, Tada Y, Mori K, Oka S, Katsumaru H. Ultrastructural localization of telencephalin, a telencephalon-specific membrane glycoprotein, in rabbit olfactory bulb. Neurosci Res. 1991;11(2):141-145.
[79] Imamura K, Mori K, Oka S, Watanabe Y. Variations by layers and developmental changes in expression of telencephalin in the visual cortex of cat. Neurosci Lett. 1990;119(1):118-121.
[80] Benson DL, Yoshihara Y, Mori K. Polarized distribution and cell type-specific localization of telencephalin, an intercellular adhesion molecule. J Neurosci Res.1998;52(1):43-53.
[81] Arii N, Mizuguchi M, Mori K, Takashima S. Development of telencephalin in the human cerebrum. Microsc Res Tech. 1999;46(1): 18-23.
[82] Sakurai E, Hashikawa T, Yoshihara Y, Kaneko S, Satoh M, Mori K.Involvement of dendritic adhesion molecule telencephalin in hippocampal long-term potentiation. Neuroreport. 1998;9(5):881-886.
[83] Tamada A, Yoshihara Y, Mori K. Dendrite-associated cell adhesion molecule,telencephalin, promotes neurite outgrowth in mouse embryo. Neurosci Lett.1998;240(3):163-166.
[84] Tian L, Nyman H, Kilgannon P, Yoshihara Y, Mori K, Andersson LC, Kaukinen S, Rauvala H, Gallatin WM, Gahmberg CG. Intercellular adhesion molecule-5 induces dendritic outgrowth by homophilic adhesion. J Cell Biol.2000;150(1):243-252.
[85] Matsuno H, Okabe S, Mishina M, Yanagida T, Mori K, Yoshihara Y.Telencephalin slows spine maturation. J Neurosci. 2006;26(6):1776-1786.
[86] 黄培堂等译. 分子克隆. 北京, 2002.
[87] Chen GJ, Xu J, Lahousse SA, Caggiano NL, de la Monte SM. Transient hypoxia causes Alzheimer-type molecular and biochemical abnormalities in cortical neurons: potential strategies for neuroprotection. J Alzheimers Dis. 2003;5(3):209-228.
[88] Thinakaran G, Borchelt DR, Lee MK, Slunt HH, Spitzer L, Kim G, Ratovitsky T, Davenport F, Nordstedt C, Seeger M, Hardy J, Levey AI, Gandy SE, Jenkins NA,Copeland NG, Price DL, Sisodia SS. Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron. 1996;17(1): 181-190.
[89] Thinakaran G, Harris CL, Ratovitski T, Davenport F, Slunt HH, Price DL,Borchelt DR, Sisodia SS. Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors. J Biol Chem.1997;272(45):28415-28422.
[90] Kim TW, Pettingell WH, Hallmark OG, Moir RD, Wasco W, Tanzi RE.Endoproteolytic cleavage and proteasomal degradation of presenilin 2 in transfected cells. J Biol Chem. 1997;272(17):11006-11010.
[91] Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G,Johnson-Wood K, Lee M, Seubert P, Davis A, Kholodenko D, Motter R, Sherrington R,Perry B, Yao H, Strome R, Lieberburg I, Rommens J, Kim S, Schenk D, Fraser P, St George Hyslop P, Selkoe DJ. Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nat Med. 1997;3(1):67-72.
[92] Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J, Hutton M, Buee L,Harigaya Y, Yager D, Morgan D, Gordon MN, Holcomb L, Refolo L, Zenk B, Hardy J,Younkin S. Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1.Nature. 1996;383(6602):710-713.
[93] Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD,Hardy J, Hutton M, Kukull W, Larson E, Levy-Lahad E, Viitanen M, Peskind E,Poorkaj P, Schellenberg G, Tanzi R, Wasco W, Lannfelt L, Selkoe D, Younkin S. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat Med. 1996;2(8):864-870.
[94] Busciglio J, Lorenzo A, Yankner BA. Methodological variables in the assessment of beta amyloid neurotoxiciry. Neurobiol Aging. 1992;13(5):609-612.
[95] Emre M, Geula C, Ransil BJ, Mesulam MM. The acute neurotoxicity and effects upon cholinergic axons of intracerebrally injected beta-amyloid in the rat brain.Neurobiol Aging. 1992;13(5):553-559.
[96] Kowall NW, Beal MF, Busciglio J, Duffy LK, Yankner BA. An in vivo model for the neurodegenerative effects of beta amyloid and protection by substance P. Proc Natl Acad Sci U S A. 1991;88(16):7247-7251.
[97] Lorenzo A, Yankner BA. Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. Proc Natl Acad Sci U S A. 1994;91(25):12243-12247.
[98] Pike CJ, Walencewicz-Wasserman AJ, Kosmoski J, Cribbs DH, Glabe CG,Cotman CW. Structure-activity analyses of beta-amyloid peptides: contributions of the beta 25-35 region to aggregation and neurotoxicity. J Neurochem. 1995;64(l):253-265.
[99] Maurice T, Su TP, Privat A. Sigmal (sigma 1) receptor agonists and neurosteroids attenuate B25-35-amyloid peptide-induced amnesia in mice through a common mechanism. Neuroscience. 1998;83(2):413-428.
[100] Stepanichev MY, Moiseeva YV, Lazareva NA, Onufriev MV, Gulyaeva NV. Single intracerebroventricular administration of amyloid-beta (25-35) peptide induces impairment in short-term rather than long-term memory in rats. Brain Res Bull.2003;61(2):197-205.
[101] Cheng G, Whitehead SN, Hachinski V, Cechetto DF. Effects of pyrrolidine dithiocarbamate on beta-amyloid (25-35)-induced inflammatory responses and memory deficits in the rat. Neurobiol Dis. 2006;23(l):140-151.
[102] Nie BM, Jiang XY, Cai JX, Fu SL, Yang LM, Lin L, Hang Q, Lu PL, Lu Y. Panaxydol and panaxynol protect cultured cortical neurons against Abeta25-35-induced toxicity. Neuropharmacology. 2008;54(5):845-853.
[103] Mook-Jung I, Joo I, Sohn S, Kwon HJ, Huh K, Jung MW. Estrogen blocks neurotoxic effects of beta-amyloid (1-42) and induces neurite extension on B103 cells.Neurosci Lett. 1997;235(3):101-104.
[104] Puttfarcken PS, Manelli AM, Neilly J, Frail DE. Inhibition of age-induced beta-amyloid neurotoxicity in rat hippocampal cells. Exp Neurol. 1996;138(1):73-81.
[105] Mueller-Steiner S, Zhou Y, Arai H, Roberson ED, Sun B, Chen J, Wang X,Yu G, Esposito L, Mucke L, Gan L. Antiamyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimer's disease. Neuron. 2006;51(6):703-714.
[106] Annaert WG, Esselens C, Baert V, Boeve C, Snellings G, Cupers P,Craessaerts K, De Strooper B. Interaction with telencephalin and the amyloid precursor protein predicts a ring structure for presenilins. Neuron. 2001;32(4):579-589.
[107] Esselens C, Oorschot V, Baert V, Raemaekers T, Spittaels K, Serneels L,Zheng H, Saftig P, De Strooper B, Klumperman J, Annaert W. Presenilin 1 mediates the turnover of telencephalin in hippocampal neurons via an autophagic degradative pathway. J Cell Biol. 2004;166(7):1041-1054.
[108] Pike CJ, Burdick D, Walencewicz AJ, Glabe CG, Cotman CW.Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state. J Neurosci. 1993; 13(4): 1676-1687.
[109] Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR,Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS,Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O'Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W,Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T. Inflammation and Alzheimer's disease.Neurobiol Aging. 2000;21(3):383-421.
[110] LaFerla FM, Green KN, Oddo S. Intracellular amyloid-beta in Alzheimer's disease. Nat Rev Neurosci. 2007;8(7):499-509.
[111] Wegiel J, Kuchna I,Nowicki K, Frackowiak J, Mazur-Kolecka B, Imaki H,Mehta PD, Silverman WP, Reisberg B, Deleon M, Wisniewski T, Pirttilla T, Frey H,Lehtimaki T, Kivimaki T, Visser FE, Kamphorst W, Potempska A, Bolton D, Currie JR,Miller DL. Intraneuronal Abeta immunoreactivity is not a predictor of brain amyloidosis-beta or neurofibrillary degeneration. Acta Neuropathol.2007;113(4):389-402.
[112] Esler WP, Wolfe MS. A portrait of Alzheimer secretases—new features and familiar faces. Science. 2001;293(5534):1449-1454.
[113] Haass C, Selkoe DJ. Cellular processing of beta-amyloid precursor protein and the genesis of amyloid beta-peptide. Cell. 1993;75(6):1039-1042.
[114] Selkoe DJ. The cell biology of beta-amyloid precursor protein and presenilin in Alzheimer's disease. Trends Cell Biol. 1998;8(11):447-453.
[115] Tanzi RE, Moir RD, Wagner SL. Clearance of Alzheimer's Abeta peptide:the many roads to perdition. Neuron. 2004;43(5):605-608.
[116] De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G,Annaert W, Von Figura K, Van Leuven F. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature. 1998;391(6665):387-390.
[117] Li X, Greenwald I. Additional evidence for an eight-transmembrane-domain topology for Caenorhabditis elegans and human presenilins. Proc Natl Acad Sci U S A. 1998;95(12):7109-7114.
[118] Laudon H, Hansson EM, Melen K, Bergman A, Farmery MR, Winblad B,Lendahl U, von Heijne G, Naslund J. A nine-transmembrane domain topology for presenilin 1. J Biol Chem. 2005;280(42):35352-35360.
[119] Henricson A, Kail L, Sonnhammer EL. A novel transmembrane topology of presenilin based on reconciling experimental and computational evidence. FEBS J.2005;272(11):2727-2733.
[120] De Strooper B. Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex. Neuron. 2003;38(l):9-12.
[121] Selkoe DJ, Wolfe MS. Presenilin: running with scissors in the membrane.Cell. 2007; 131(2):215-221.
[122] Annaert W, De Strooper B. A cell biological perspective on Alzheimer's disease. Annu Rev Cell Dev Biol. 2002; 18:25-51.
[123] Selkoe D, Kopan R. Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. Annu Rev Neurosci. 2003;26:565-597.
[124] Annaert W, De Strooper B. Presenilins: molecular switches between proteolysis and signal transduction. Trends Neurosci. 1999;22(10):439-443.
[125] Brown MS, Ye J, Rawson RB, Goldstein JL. Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell.2000;100(4):391-398.
[126] Lindsberg PJ, Launes J, Tian L, Valimaa H, Subramanian V, Siren J, Hokkanen L,Hyypia T,Carpen O,Gahmberg CG.Release of soluble ICAM-5,a neuronal adhesion molecule,in acute encephalitis.Neurology.2002;58(3):446-451.
[127]Petratos S,Li QX,George AJ,Hou X,Kerr ML,Unabia SE,Hatzinisiriou I,Maksel D,Aguilar MI,Small DH.The beta-amyloid protein of Alzheimer's disease increases neuronal CRMP-2 phosphorylation by a Rho-GTP mechanism.Brain.2008;131(Pt 1):90-108.
[128]Lai CS,Yu MS,Yuen WH,So KF,Zee SY,Chang RC.Antagonizing beta-amyloid peptide neurotoxicity of the anti-aging fungus Ganoderma lucidum.Brain Res.2008;1190:215-224.
[129]Hu M,Schurdak ME,Puttfarcken PS,El Kouhen R,Gopalakrishnan M,Li J.High content screen microscopy analysis of A beta 1-42-induced neurite outgrowth reduction in rat primary cortical neurons:neuroprotective effects of alpha 7 neuronal nicotinic acetylcholine receptor ligands.Brain Res.2007;1151:227-235.
[130]Arun P,Madhavarao CN,Moffett JR,Namboodiri MA.Regulation of N-acetylaspartate and N-acetylaspartylglutamate biosynthesis by protein kinase activators.J Neurochem.2006;98(6):2034-2042.
[131]Nyman-Huttunen H,Tian L,Ning L,Gahmberg CG.alpha-Actinin-dependent cytoskeletal anchorage is important for ICAM-5-mediated neuritic outgrowth.J Cell Sci.2006;119(Pt 15):3057-3066.
[132]Masliah E,Alford M,Adame A,Rockenstein E,Galasko D,Salmon D,Hansen LA,Thal LJ.Abetal-42 promotes cholinergic sprouting in patients with AD and Lewy body variant of AD.Neurology.2003;61(2):206-211.
[133]Evans NA,Facci L,Owen DE,Soden PE,Burbidge SA,Prinjha RK,Richardson JC,Skaper SD.Abeta(1-42) reduces synapse number and inhibits neurite outgrowth in primary cortical and hippocampal neurons:a quantitative analysis.J Neurosci Methods.2008;175(1):96-103.
[134]Lin H,Bhatia R,Lal R.Amyloid beta protein forms ion channels:implications for Alzheimer's disease pathophysiology.FASEB J.2001;15(13):2433-2444.
[135]Kuboyama T,Tohda C,Komatsu K.Withanoside IV and its active metabolite, sominone, attenuate Abeta(25-35)-induced neurodegeneration. Eur J Neurosci. 2006;23(6):1417-1426.
[136] Klementiev B, Novikova T, Novitskaya V, Walmod PS, Dmytriyeva O,Pakkenberg B, Berezin V, Bock E. A neural cell adhesion molecule-derived peptide reduces neuropathological signs and cognitive impairment induced by Abeta25-35.Neuroscience. 2007;145(1):209-224.
[137] Tohda C, Matsumoto N, Zou K, Meselhy MR, Komatsu K.Abeta(25-35)-induced memory impairment, axonal atrophy, and synaptic loss are ameliorated by Ml, A metabolite of protopanaxadiol-type saponins.Neuropsychopharmacology. 2004;29(5):860-868.
[138] Tohda C, Ichimura M, Bai Y, Tanaka K, Zhu S, Komatsu K. Inhibitory effects of Eleutherococcus senticosus extracts on amyloid beta(25-35)-induced neuritic atrophy and synaptic loss. J Pharmacol Sci. 2008;107(3):329-339.
[139] Ziv NE, Smith SJ. Evidence for a role of dendritic filopodia in synaptogenesis and spine formation. Neuron. 1996;17(1):91-102.
[140] Fiala JC, Feinberg M, Popov V, Harris KM. Synaptogenesis via dendritic filopodia in developing hippocampal area CA1. J Neurosci. 1998;18(21):8900-8911.
[141] Dailey ME, Smith SJ. The dynamics of dendritic structure in developing hippocampal slices. J Neurosci. 1996;16(9):2983-2994.
[142] Dunaevsky A, Tashiro A, Majewska A, Mason C, Yuste R. Developmental regulation of spine motility in the mammalian central nervous system. Proc Natl Acad Sci U S A. 1999;96(23):13438-13443.
[143] Lendvai B, Stern EA, Chen B, Svoboda K. Experience-dependent plasticity of dendritic spines in the developing rat barrel cortex in vivo. Nature.2000;404(6780):876-881.
[144] Yuste R, Bonhoeffer T. Genesis of dendritic spines: insights from ultrastructural and imaging studies. Nat Rev Neurosci. 2004;5(1):24-34.
[145] Harris KM, Kater SB. Dendritic spines: cellular specializations imparting both stability and flexibility to synaptic function. Annu Rev Neurosci. 1994;17:341-371.
[146] Mitsui S, Saito M, Hayashi K, Mori K, Yoshihara Y. A novel phenylalanine-based targeting signal directs telencephalin to neuronal dendrites.J Neurosci.2005;25(5):1122-1131.
[147]Ferreiro E,Oliveira CR,Pereira CM.The release of calcium from the endoplasmic reticulum induced by amyloid-beta and prion peptides activates the mitochondrial apoptotic pathway.Neurobiol Dis.2008;30(3):331-342.
[148]Lloret A,Badia MC,Mora NJ,Ortega A,Pallardo FV,Alonso MD,Atamna H,Vina J.Gender and age-dependent differences in the mitochondrial apoptogenic pathway in Alzheimer's disease.Free Radic Biol Med.2008;44(12):2019-2025.
[149]Nakamura M,Nakashima S,Katagiri Y,Nozawa Y.Effect of wortmannin and 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one(LY294002) on N-formyl-methionyl-leucyl-phenylalanine-induced phospholipase D activation in differentiated HL60 cells:possible involvement of phosphatidylinositol 3-kinase in phospholipase D activation.Biochem Pharmacol.1997;53(12):1929-1936.
[150]Vlahos CJ,Matter WF,Hui KY,Brown RF.A specific inhibitor of phosphatidylinositol 3-kinase,2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002).J Biol Chem.1994;269(7):5241-5248.
[151]Milosevic I,Sorensen JB,Lang T,Krauss M,Nagy G,Haucke V,Jahn R,Neher E.Plasmalemmal phosphatidylinositol-4,5-bisphosphate level regulates the releasable vesicle pool size in chromaffin cells.J Neurosci.2005;25(10):2557-2565.
[152]Vukic V,Callaghan D,Walker D,Lue LF,Liu QY,Couraud PO,Romero IA,Weksler B,Stanimirovic DB,Zhang W.Expression of inflammatory genes induced by beta-amyloid peptides in human brain endothelial cells and in Alzheimer's brain is mediated by the JNK-AP1 signaling pathway.Neurobiol Dis.2009;34(1):95-106.
[153]Merry DE,Korsmeyer SJ.Bcl-2 gene family in the nervous system.Annu Rev Neurosci.1997;20:245-267.
[154]Zhang Y,McLaughlin R,Goodyer C,LeBlanc A.Selective cytotoxicity of intracellular amyloid beta peptide1-42 through p53 and Bax in cultured primary human neurons.J Cell Biol.2002;156(3):519-529.
[155]Fiala M,Zhang L,Gan X,Sherry B,Taub D,Graves MC,Hama S,Way D, Weinand M, Witte M, Lorton D, Kuo YM, Roher AE. Amyloid-beta induces chemokine secretion and monocyte migration across a human blood—brain barrier model. Mol Med.1998;4(7):480-489.
[156] Mattioli B, Straface E, Quaranta MG, Giordani L, Viora M. Leptin promotes differentiation and survival of human dendritic cells and licenses them for Th1 priming. J Immunol. 2005;174(11):6820-6828.
[157] Gillardon F, Wickert H, Zimmermann M. Up-regulation of bax and down-regulation of bcl-2 is associated with kainate-induced apoptosis in mouse brain.Neurosci Lett. 1995;192(2):85-88.
[158] Grad JM, Zeng XR, Boise LH. Regulation of Bcl-xL: a little bit of this and a little bit of STAT. Curr Opin Oncol. 2000;12(6):543-549.
[159] Sun X, Liu Y, Hu G, Wang H. Protective effects of nicotine against glutamate-induced neurotoxicity in PC12 cells. Cell Mol Biol Lett. 2004;9(3):409-422.
[160] Song YS, Park HJ, Kim SY, Lee SH, Yoo HS, Lee HS, Lee MK, Oh KW,Kang SK, Lee SE, Hong JT. Protective role of Bcl-2 on beta-amyloid-induced cell death of differentiated PC 12 cells: reduction of NF-kappaB and p38 MAP kinase activation.Neurosci Res. 2004;49(1):69-80.
[161] Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES,Wang X. Cytochrome c and dATP-dependent formation of Apaf-l/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997;91(4):479-489.
[162] Marrero MB, Bencherif M. Convergence of alpha 7 nicotinic acetylcholine receptor-activated pathways for anti-apoptosis and anti-inflammation: central role for JAK2 activation of STAT3 and NF-kappaB. Brain Res. 2009;1256:1-7.
[163] Morais Cardoso S, Swerdlow RH, Oliveira CR. Induction of cytochrome c-mediated apoptosis by amyloid beta 25-35 requires functional mitochondria. Brain Res. 2002;931(2):117-125.
[164] Sperandio S, de Belle I, Bredesen DE. An alternative, nonapoptotic form of programmed cell death. Proc Natl Acad Sci U S A. 2000;97(26):14376-14381.
[165] Brunet A, Datta SR, Greenberg ME. Transcription-dependent and-independent control of neuronal survival by the PI3K-Akt signaling pathway. Curr Opin Neurobiol. 2001;11(3):297-305.
[166] Shimoke K, Kishi S, Utsumi T, Shimamura Y, Sasaya H, Oikawa T,Uesato S, Ikeuchi T. NGF-induced phosphatidylinositol 3-kinase signaling pathway prevents thapsigargin-triggered ER stress-mediated apoptosis in PC12 cells. Neurosci Lett.2005;389(3):124-128.
[167] Lee KY, Koh SH, Noh MY, Kim SH, Lee YJ.Phosphatidylinositol-3-kinase activation blocks amyloid beta-induced neurotoxicity.Toxicology. 2008;243(1-2):43-50.
[168] Perez OD, Kinoshita S, Hitoshi Y, Payan DG, Kitamura T, Nolan GP,Lorens JB. Activation of the PKB/AKT pathway by ICAM-2. Immunity.2002;16(1):51-65.
[169] Sakakibara T, Hibi K, Kodera Y, Ito K, Akiyama S, Nakao A.Plasminogen activator inhibitor-1 as a potential marker for the malignancy of esophageal squamous cell carcinoma. Clin Cancer Res. 2004;10(4):1375-1378.
[170] Mitsui S, Saito M, Mori K, Yoshihara Y. A transcriptional enhancer that directs telencephalon-specific transgene expression in mouse brain. Cereb Cortex.2007;17(3):522-530.
[171] Arpin M, Algrain M, Louvard D. Membrane-actin microfilament connections: an increasing diversity of players related to band 4.1. Curr Opin Cell Biol.1994;6(1):136-141.
[172] Bretscher A, Reczek D, Berryman M. Ezrin: a protein requiring conformational activation to link microfilaments to the plasma membrane in the assembly of cell surface structures. J Cell Sci. 1997;110 (Pt 24):3011-3018.
[173] Tsukita S, Yonemura S. ERM proteins: head-to-tail regulation of actin-plasma membrane interaction. Trends Biochem Sci. 1997;22(2):53-58.
[174] Tsukita S, Yonemura S. ERM (ezrin/radixin/moesin) family: from cytoskeleton to signal transduction. Curr Opin Cell Biol. 1997;9(1):70-75.
[175] Vaheri A, Carpen O, Heiska L, Helander TS, Jaaskelainen J,Majander-Nordenswan P, Sainio M, Timonen T, Turunen O. The ezrin protein family:membrane-cytoskeleton interactions and disease associations. Curr Opin Cell Biol. 1997;9(5):659-666.
[176] Bretscher A. Regulation of cortical structure by the ezrin-radixin-moesin protein family. Curr Opin Cell Biol. 1999;11(1):109-116.
[177] Mangeat P, Roy C, Martin M. ERM proteins in cell adhesion and membrane dynamics. Trends Cell Biol. 1999;9(5):187-192.
[178] Tsukita S, Yonemura S. Cortical actin organization: lessons from ERM (ezrin/radixin/moesin) proteins. J Biol Chem. 1999;274(49):34507-34510.
[179] Yonemura S, Nagafuchi A, Sato N, Tsukita S. Concentration of an integral membrane protein, CD43 (leukosialin, sialophorin), in the cleavage furrow through the interaction of its cytoplasmic domain with actin-based cytoskeletons. J Cell Biol.1993;120(2):437-449.
[180] Tsukita S, Oishi K, Sato N, Sagara J, Kawai A. ERM family members as molecular linkers between the cell surface glycoprotein CD44 and actin-based cytoskeletons. J Cell Biol. 1994;126(2):391-401.
[181] Helander TS, Carpen O, Turunen O, Kovanen PE, Vaheri A, Timonen T. ICAM-2 redistributed by ezrin as a target for killer cells. Nature.1996;382(6588):265-268.
[182] Hirao M, Sato N, Kondo T, Yonemura S, Monden M, Sasaki T, Takai Y,Tsukita S. Regulation mechanism of ERM (ezrin/radixin/moesin) protein/plasma membrane association: possible involvement of phosphatidylinositol turnover and Rho-dependent signaling pathway. J Cell Biol. 1996;135(1):37-51.
[183] Yonemura S, Hirao M, Doi Y, Takahashi N, Kondo T, Tsukita S.Ezrin/radixin/moesin (ERM) proteins bind to a positively charged amino acid cluster in the juxta-membrane cytoplasmic domain of CD44, CD43, and ICAM-2. J Cell Biol.1998;140(4):885-895.
[184] Bretscher A, Edwards K, Fehon RG. ERM proteins and merlin: integrators at the cell cortex. Nat Rev Mol Cell Biol. 2002;3(8):586-599.
[185] Turunen O, Wahlstrom T, Vaheri A. Ezrin has a COOH-terminal actin-binding site that is conserved in the ezrin protein family. J Cell Biol.1994;126(6):1445-1453.
[186] Pestonjamasp K, Amieva MR, Strassel CP, Nauseef WM, Furthmayr H,Luna EJ. Moesin, ezrin, and p205 are actin-binding proteins associated with neutrophil plasma membranes. Mol Biol Cell. 1995;6(3):247-259.
[187] Roy C, Martin M, Mangeat P. A dual involvement of the amino-terminal domain of ezrin in F- and G-actin binding. J Biol Chem. 1997;272(32):20088-20095.
[188] Martin M, Roy C, Montcourrier P, Sahuquet A, Mangeat P. Three determinants in ezrin are responsible for cell extension activity. Mol Biol Cell.1997;8(8):1543-1557.
[189] Nakamura F, Amieva MR, Furthmayr H. Phosphorylation of threonine 558 in the carboxyl-terminal actin-binding domain of moesin by thrombin activation of human platelets. J Biol Chem. 1995;270(52):31377-31385.
[190] Hayashi K, Yonemura S, Matsui T, Tsukita S. Immunofluorescence detection of ezrin/radixin/moesin (ERM) proteins with their carboxyl-terminal threonine phosphorylated in cultured cells and tissues. J Cell Sci. 1999;112 (Pt 8):1149-1158.
[191] Stapleton G, Malliri A, Ozanne BW. Downregulated AP-1 activity is associated with inhibition of Protein-Kinase-C-dependent CD44 and ezrin localisation and upregulation of PKC theta in A431 cells. J Cell Sci. 2002; 115(Pt 13):2713-2724.
[192] Martin TA, Harrison G, Mansel RE, Jiang WG. The role of the CD44/ezrin complex in cancer metastasis. Crit Rev Oncol Hematol. 2003;46(2):165-186.
[193] Polesello C, Payre F. Small is beautiful: what flies tell us about ERM protein function in development. Trends Cell Biol. 2004;14(6):294-302.
[194] Kivela T, Jaaskelainen J, Vaheri A, Carpen O. Ezrin, a membrane-organizing protein, as a polarization marker of the retinal pigment epithelium in vertebrates. Cell Tissue Res. 2000;301(2):217-223.
[195] Mangeat P, Roy C, Martin M. ERM proteins in cell adhesion and membrane dynamics: Authors' correction. Trends Cell Biol. 1999;9(7):289.
[196] Matsui T, Maeda M, Doi Y, Yonemura S, Amano M, Kaibuchi K, Tsukita S. Rho-kinase phosphorylates COOH-terminal threonines of ezrin/radixin/moesin (ERM) proteins and regulates their head-to-tail association. J Cell Biol.1998;140(3):647-657.
[197] Gautreau A, Louvard D, Arpin M. Morphogenic effects of ezrin require a phosphorylation-induced transition from oligomers to monomers at the plasma membrane. J Cell Biol. 2000;150(1):193-203.
[198] Otey CA, Carpen 0. Alpha-actinin revisited: a fresh look at an old player.Cell Motil Cytoskeleton. 2004;58(2):104-111.
[199] Cant SH, Pitcher JA. G protein-coupled receptor kinase 2-mediated phosphorylation of ezrin is required for G protein-coupled receptor-dependent reorganization of the actin cytoskeleton. Mol Biol Cell. 2005;16(7):3088-3099.
[200] Papakonstanti EA, Stournaras C. Cell responses regulated by early reorganization of actin cytoskeleton. FEBS Lett. 2008;582(14):2120-2127.
[201] Fievet BT, Gautreau A, Roy C, Del Maestro L, Mangeat P, Louvard D,Arpin M. Phosphoinositide binding and phosphorylation act sequentially in the activation mechanism of ezrin. J Cell Biol. 2004;164(5):653-659.
[202] Khanna C, Wan X, Bose S, Cassaday R, Olomu O, Mendoza A, Yeung C,Gorlick R, Hewitt SM, Helman LJ. The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nat Med. 2004;10(2):182-186.
[203] Yu Y, Khan J, Khanna C, Helman L, Meltzer PS, Merlino G. Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators. Nat Med. 2004;10(2):175-181.
[204] Doi Y, Itoh M, Yonemura S, Ishihara S, Takano H, Noda T, Tsukita S.Normal development of mice and unimpaired cell adhesion/cell motility/actin-based cytoskeleton without compensatory up-regulation of ezrin or radixin in moesin gene knockout. J Biol Chem. 1999;274(4):2315-2321.
[205] Pene F, Claessens YE, Muller O, Viguie F, Mayeux P, Dreyfus F,Lacombe C, Bouscary D. Role of the phosphatidylinositol 3-kinase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apoptosis in multiple myeloma. Oncogene. 2002;21(43):6587-6597.
[206] Corvera S, Czech MP. Direct targets of phosphoinositide 3-kinase products in membrane traffic and signal transduction. Trends Cell Biol. 1998;8(11):442-446.
[207] Coffer PJ, Geijsen N, M'Rabet L, Schweizer RC, Maikoe T, Raaijmakers JA, Lammers JW, Koenderman L. Comparison of the roles of mitogen-activated protein kinase kinase and phosphatidylinositol 3-kinase signal transduction in neutrophil effector function. Biochem J. 1998;329 (Pt 1):121-130.
[208] Coffer PJ, Jin J, Woodgett JR. Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation. Biochem J. 1998;335 (Pt 1):1-13.
[209] Cantley LC. The phosphoinositide 3-kinase pathway. Science.2002;296(5573):1655-1657.
[210] Osaki M, Oshimura M, Ito H. PI3K-Akt pathway: its functions and alterations in human cancer. Apoptosis. 2004;9(6):667-676.
[211] Edwards LA, Thiessen B, Dragowska WH, Daynard T, Bally MB, Dedhar S. Inhibition of ILK in PTEN-mutant human glioblastomas inhibits PKB/Akt activation, induces apoptosis, and delays tumor growth. Oncogene. 2005;24(22):3596-3605.
[212] Song G, Ouyang G, Bao S. The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med. 2005;9(l):59-71.
[213] Huang S, Houghton PJ. Targeting mTOR signaling for cancer therapy.Curr Opin Pharmacol. 2003;3(4):371-377.
[214] Zhou X, Tan M, Stone Hawthorne V, Klos KS, Lan KH, Yang Y, Yang W, Smith TL, Shi D, Yu D. Activation of the Akt/mammalian target of rapamycin/4E-BPl pathway by ErbB2 overexpression predicts tumor progression in breast cancers. Clin Cancer Res. 2004;10(20):6779-6788.
[215] Asnaghi L, Bruno P, Priulla M, Nicolin A. mTOR: a protein kinase switching between life and death. Pharmacol Res. 2004;50(6):545-549.
[216] Schalm SS, Fingar DC, Sabatini DM, Blenis J. TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr Biol.2003;13(10):797-806.
[217] Xu G, Zhang W, Bertram P, Zheng XF, McLeod H. Pharmacogenomic profiling of the PI3K/PTEN-AKT-mTOR pathway in common human tumors. Int J Oncol. 2004;24(4):893-900.
[218] Gao N, Flynn DC, Zhang Z, Zhong XS, Walker V, Liu KJ, Shi X, Jiang BH. Gl cell cycle progression and the expression of Gl cyclins are regulated by PI3K/AKT/mTOR/p70S6Kl signaling in human ovarian cancer cells. Am J Physiol Cell Physiol. 2004;287(2):C281-291.
[219] Franke TF, Hornik CP, Segev L, Shostak GA, Sugimoto C. PI3K/Akt and apoptosis: size matters. Oncogene. 2003;22(56):8983-8998.
[220] Persad S, Dedhar S. The role of integrin-linked kinase (ILK) in cancer progression. Cancer Metastasis Rev. 2003;22(4):375-384.
[221] Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P,Hemmings BA. Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 1996;15(23):6541-6551.
[222] Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts.Genes Dev. 1999;13(22):2905-2927.
[223] Nicholson KM, Anderson NG. The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal. 2002;14(5):381-395.
[224] Takada-Takatori Y, Kume T, Sugimoto M, Katsuki H, Sugimoto H,Akaike A. Acetylcholinesterase inhibitors used in treatment of Alzheimer's disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade. Neuropharmacology. 2006;51(3):474-486.
[225] Gross A, McDonnell JM, Korsmeyer SJ. BCL-2 family members and the mitochondria in apoptosis. Genes Dev. 1999;13(15):1899-1911.
[226] Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME.Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997;91(2):231-241.
[227] del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G.Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science.1997;278(5338):687-689.
[228] Matsuzaki H, Tamatani M, Mitsuda N, Namikawa K, Kiyama H, Miyake S,Tohyama M. Activation of Akt kinase inhibits apoptosis and changes in Bcl-2 and Bax expression induced by nitric oxide in primary hippocampal neurons. J Neurochem.1999;73(5):2037-2046.
[229] Gardai SJ, Hildeman DA, Frankel SK, Whitlock BB, Frasch SC, Borregaard N, Marrack P, Bratton DL, Henson PM. Phosphorylation of Bax Ser184 by Akt regulates its activity and apoptosis in neutrophils. J Biol Chem.2004;279(20):21085-21095.
[230] Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell.1993;74(4):609-619.
[231] Zhang Z, Lapolla SM, Annis MG, Truscott M, Roberts GJ, Miao Y, Shao Y, Tan C, Peng J, Johnson AE, Zhang XC, Andrews DW, Lin J. Bcl-2 homodimerization involves two distinct binding surfaces, a topographic arrangement that provides an effective mechanism for Bcl-2 to capture activated Bax. J Biol Chem.2004;279(42):43920-43928.
[232] Jeong SY, Gaume B, Lee YJ, Hsu YT, Ryu SW, Yoon SH, Youle RJ.Bcl-x(L) sequesters its C-terminal membrane anchor in soluble, cytosolic homodimers.EMBO J. 2004;23(10):2146-2155.
[233] Sadidi M, Lentz SI, Feldman EL. Hydrogen Peroxide-Induced Akt Phosphorylation Regulates Bax Activation. Biochimie. 2009.
[234] Won CK, Ha SJ, Noh HS, Kang SS, Cho GJ, Choi WS, Koh PO. Estradiol prevents the injury-induced decrease of Akt activation and Bad phosphorylation.Neurosci Lett. 2005;387(2):115-119.
[235] Hu Z, Sayeed MM. Activation of PI3-kinase/PKB contributes to delay in neutrophil apoptosis after thermal injury. Am J Physiol Cell Physiol.2005;288(5):C1171-1178.
[236] Xin M, Deng X. Nicotine inactivation of the proapoptotic function of Bax through phosphorylation. J Biol Chem. 2005;280(11):10781-10789.
[237] Mayo LD, Dormer DB. The PTEN, Mdm2, p53 tumor suppressor-oncoprotein network. Trends Biochem Sci. 2002;27(9):462-467.
[238] Wee KB, Aguda BD. Akt versus p53 in a network of oncogenes and tumor suppressor genes regulating cell survival and death. Biophys J. 2006;91(3):857-865.
[239] Gibson EM, Henson ES, Haney N, Villanueva J, Gibson SB. Epidermal growth factor protects epithelial-derived cells from tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by inhibiting cytochrome c release. CancerRes. 2002;62(2):488-496.
[240] Kim EC, Yun BS, Ryoo IJ, Min JK, Won MH, Lee KS, Kim YM, Yoo ID,Kwon YG. Complestatin prevents apoptotic cell death: inhibition of a mitochondrial caspase pathway through AKT/PKB activation. Biochem Biophys Res Commun.2004;313(1):193-204.
[241] Honda K, Shimohama S, Sawada H, Kihara T, Nakamizo T, Shibasaki H,Akaike A. Nongenomic antiapoptotic signal transduction by estrogen in cultured cortical neurons. J Neurosci Res. 2001;64(5):466-475.
[242] Maruya SI, Myers JN, Weber RS, Rosenthal DI, Lotan R, El-Naggar AK.ICAM-5 (telencephalin) gene expression in head and neck squamous carcinoma tumorigenesis and perineural invasion! Oral Oncol. 2005;41(6):580-588.
[243] Delcommenne M, Tan C, Gray V, Rue L, Woodgett J, Dedhar S. Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Proc Natl Acad Sci U S A.1998;95(19):11211-11216.
[244] Walker EH, Pacold ME, Perisic O, Stephens L, Hawkins PT, Wymann MP,Williams RL. Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell.2000;6(4):909-919.
[245] Liu P, Xu B, Li J, Lu H. LY294002 inhibits leukemia cell invasion and migration through early growth response gene 1 induction independent of phosphatidylinositol 3-kinase-Akt pathway. Biochem Biophys Res Commun.2008;377(1):187-190.
[246] Sun H, Xu B, Sheveleva E, Chen QM. LY294002 inhibits glucocorticoid-induced COX-2 gene expression in cardiomyocytes through a phosphatidylinositol 3 kinase-independent mechanism. Toxicol Appl Pharmacol.2008;232(1):25-32.
[247] Poh TW, Pervaiz S. LY294002 and LY303511 sensitize tumor cells to drug-induced apoptosis via intracellular hydrogen peroxide production independent of the phosphoinositide 3-kinase-Akt pathway.Cancer Res.2005;65(14):6264-6274.
[248]Kulik G,Carson JP,Vomastek T,Overman K,Gooch BD,Srinivasula S,Alnemri E,Nunez G,Weber MJ.Tumor necrosis factor alpha induces BID cleavage and bypasses antiapoptotic signals in prostate cancer LNCaP cells.Cancer Res.2001;61(6):2713-2719.
[249]Brognard J,Clark AS,Ni Y,Dennis PA.Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation.Cancer Res.2001;61(10):3986-3997.
[1] Selkoe,D.J., The molecular pathology of Alzheimer's disease, Neuron, 6 (1991)487-498.
[2] Terry,R.D., Masliah,E., Salmon,D.P., Butters,N., DeTeresa,R., Hill,R.,Hansen,L.A. and Katzman,R., Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment, Ann. Neurol., 30(1991) 572-580.
[3] McKee,A.C, Kosik,K.S. and Kowall,N.W., Neuritic pathology and dementia in Alzheimer's disease, Ann. Neurol., 30 (1991) 156-165.
[4] Muresan,Z. and Muresan,V., Neuritic deposits of amyloid-beta peptide in a subpopulation of central nervous system-derived neuronal cells, Mol. Cell Biol., 26(2006) 4982-4997.
[5] Whalen,B.M, Selkoe,D.J. and Hartley,D.M, Small non-fibrillar assemblies of amyloid beta-protein bearing the Arctic mutation induce rapid neuritic degeneration1,Neurobiol. Dis., 20 (2005) 254-266.
[6] Benowitz,L.I., Rodriguez,W., Paskevich,P., Mufson,E.J., Schenk,D. and Neve,R.L., The amyloid precursor protein is concentrated in neuronal lysosomes in normal and Alzheimer disease subjectsl, Exp. Neurol., 106 (1989) 237-250.
[7] McGeer,P.L., Akiyama,H., Kawamata,T., Yamada,T., Walker,D.G. and Ishii,T., Immunohistochemical localization of beta-amyloid precursor protein sequences in Alzheimer and normal brain tissue by light and electron microscopy2, J. Neurosci.Res., 31 (1992) 428-442.
[8] Jung,S.S., Nalbantoglu,J. and Cashman,N.R., Alzheimer's beta-amyloid precursor protein is expressed on the surface of immediately ex vivo brain cells: a flow cytometric studyl, J. Neurosci. Res., 46 (1996) 336-348.
[9] Kang,J., Lemaire,H.G., Unterbeck,A., SalbaumJ.M., Masters,C.L.,Grzeschik,K.H., Multhaup,G., Beyreuther,K. and Muller-Hill,B., The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor1, Nature, 325(1987)733-736.
[10] Selkoe,D.J. and Wolfe,M.S., Presenilin: running with scissors in the membrane1,Cell, 131 (2007)215-221.
[11] Esch,F.S.,Keim,P.S.,Beattie,E.C.,Blacher,R.W.,Culwell,A.R.,Oltersdorf,T.,McClure,D. and Ward,P.J., Cleavage of amyloid beta peptide during constitutive processing of its precursorl, Science, 248 (1990) 1122-1124.
[12] Selkoe,D.J., Cell biology of protein misfolding: the examples of Alzheimer's and Parkinson's diseasesl, Nat. Cell Biol., 6 (2004) 1054-1061.
[13] Wasco,W., Bupp,K., Magendantz,M., GusellaJ.F., Tanzi,R.E. and Solomon,F., Identification of a mouse brain cDNA that encodes a protein related to the Alzheimer disease-associated amyloid beta protein precursorl, Proc. Natl. Acad. Sci. U. S. A, 89(1992) 10758-10762.
[14] Wasco,W., Gurubhagavatula,S., Paradis,M.D., Romano,D.M., Sisodia,S.S.,Hyman,B.T., Neve,R.L. and Tanzi,R.E., Isolation and characterization of APLP2 encoding a homologue of the Alzheimer's associated amyloid beta protein precursor3,Nat. Genet., 5 (1993) 95-100.
[15] Walsh,D.M., FadeevaJ.V., LaVoie,M.J., Paliga,K., Eggert,S., Kimberly,W.T.,Wasco,W. and Selkoe,D.J., gamma-Secretase cleavage and binding to FE65 regulate the nuclear translocation of the intracellular C-terminal domain (ICD) of the APP family of proteinsl, Biochemistry, 42 (2003) 6664-6673.
[16] Scheinfeld,M.H., Ghersi,E., Laky,K., Fowlkes,B.J. and D'Adamio,L.,Processing of beta-amyloid precursor-like protein-1 and -2 by gamma-secretase regulates transcription 1, J. Biol. Chem., 277 (2002) 44195-44201.
[17] Eggert,S., Paliga,K., Soba,P., Evin,G., Masters,C.L., Weidemann,A. and Beyreuther,K., The proteolytic processing of the amyloid precursor protein gene family members APLP-1 and APLP-2 involves alpha-, beta-, gamma-, and epsilon-like cleavages: modulation of APLP-1 processing by n-glycosylationl, J. Biol. Chem., 279(2004) 18146-18156.
[18] Pastorino,L., Ikin,A.F., Lamprianou,S., Vacaresse,N., Revelli,J.P., Platt,K.,Paganetti,P., Mathews,P.M., Harroch,S. and Buxbaum,J.D., BACE (beta-secretase) modulates the processing of APLP2 in vivol, Mol. Cell Neurosci., 25 (2004) 642-649.
[19] Zheng,H., Jiang,M., Trumbauer,M.E., Sirinathsinghji,D.J., Hopkins,R.,Smith,D.W., Heavens,R.P., Dawson,G.R., Boyce,S., Conner,M.W., Stevens,K.A.,Slunt,H.H., Sisoda,S.S., Chen,H.Y. and Van der Ploeg,L.H., beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity1, Cell, 81 (1995)525-531.
[20] Heber,S., Herms,J., Gajic,V., Hainfellner,J., Aguzzi,A., Rulicke,T., von,K.H.,von,K.C, Sisodia,S., Tremml,P., Lipp,H.P., Wolfer,D.P. and Muller.U., Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family membersl, J. Neurosci., 20 (2000) 7951-7963.
[21] Young-Pearse,T.L., Chen,A.C, Chang,R., Marquez,C. and Selkoe,D.J.,Secreted APP regulates the function of full-length APP in neurite outgrowth through interaction with integrin betal 1, Neural Dev., 3 (2008) 15.
[22] Perez,R.G., Zheng,H., Van der Ploeg,L.H. and Koo,E.H., The beta-amyloid precursor protein of Alzheimer's disease enhances neuron viability and modulates neuronal polarityl1, J. Neurosci., 17 (1997) 9407-9414.
[23] Araki,W., Kitaguchi,N., Tokushima,Y., Ishii,K., Aratake,H., Shimohama,S., Nakamura,S. and Kimura,J., Trophic effect of beta-amyloid precursor protein on cerebral cortical neurons in culrure6, Biochem. Biophys. Res. Commun., 181 (1991)265-271.
[24] Ohsawa,I., Hirose,Y., Ishiguro,M, Imai,Y., Ishiura,S. and Kohsaka,S.,Expression, purification, and neurotrophic activity of amyloid precursor protein-secreted forms produced by yeastl, Biochem. Biophys. Res. Commun., 213(1995) 52-58.
[25] Milward,E.A., Papadopoulos,R., Fuller,S.J., Moir,R.D., Small,D., Beyreuther,K. and Masters,C.L., The amyloid protein precursor of Alzheimer's disease is a mediator of the effects of nerve growth factor on neurite outgrowthl, Neuron, 9 (1992)129-137.
[26] Wallace,W.C, Akar,C.A. and Lyons,W.E., Amyloid precursor protein potentiates the neurotrophic activity of NGF3, Brain Res. Mol. Brain Res., 52 (1997)201-212.
[27] Qiu,W.Q., Ferreira,A., Miller,C, Koo,E.H. and Selkoe,D.J., Cell-surface beta-amyloid precursor protein stimulates neurite outgrowth of hippocampal neurons in an isoform-dependent mannerl 1, J. Neurosci., 15 (1995) 2157-2167.
[28] Ando,K., Oishi,M., Takeda,S., Iijima,K., Isohara,T., Nairn,A.C, Kirino,Y.,Greengard,P. and Suzuki,T., Role of phosphorylation of Alzheimer's amyloid precursor protein during neuronal differentiation 1, J. Neurosci., 19 (1999) 4421-4427.
[29] Muresan,Z. and Muresan,V., c-Jun NH2-terminal kinase-interacting protein-3 facilitates phosphorylation and controls localization of amyloid-beta precursor protein2,J. Neurosci., 25 (2005) 3741-3751.
[30] Kibbey,M.C, Jucker,M., Weeks,B.S., Neve,R.L., Van Nostrand,W.E. and Kleinman,H.K., beta-Amyloid precursor protein binds to the neurite-promoting IKVAV site of lamininl, Proc. Natl. Acad. Sci. U. S. A, 90 (1993) 10150-10153.
[31] Annaert,W. and De,S.B., A cell biological perspective on Alzheimer's diseasel, Annu. Rev. Cell Dev. Biol., 18 (2002) 25-51.
[32] Leyssen,M., Ayaz,D., Hebert,S.S., Reeve,S., De,S.B. and Hassan,B.A.,Amyloid precursor protein promotes post-developmental neurite arborization in the Drosophila brainl, EMBO J., 24 (2005) 2944-2955.
[33] Ohsawa,I., Takamura,C. and Kohsaka,S., The amino-terminal region of amyloid precursor protein is responsible for neurite outgrowth in rat neocortical explant culturel, Biochem. Biophys. Res. Commun., 236 (1997) 59-65.
[34] Harper,SJ., Bilsland,J.G., Shearman,M.S., Zheng,H., Van der,P.L. and Sirinathsinghji,D.J., Mouse cortical neurones lacking APP show normal neurite outgrowth and survival responses in vitro2, Neuroreport, 9 (1998) 3053-3058.
[35] Masliah,E., Sisk,A., Mallory,M., Mucke,L., Schenk,D. and Games,D.,Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F beta-amyloid precursor protein and Alzheimer's disease5, J. Neurosci., 16 (1996)5795-5811.
[36] Bodendorf,U., Danner,S., Fischer,F., Stefani,M., Sturchler-Pierrat,C,Wiederhold,K.H., Staufenbiel,M. and Paganetti,P., Expression of human beta-secretase in the mouse brain increases the steady-state level of beta-amyloid2, J. Neurochem., 80 (2002) 799-806.
[37] McKee,A.C, Kosik,K.S. and Kowall,N.W., Neuritic pathology and dementia in Alzheimer's disease1, Ann. Neurol., 30 (1991) 156-165.
[38] Dickson,D.W., Farlo,J., Davies,P., Crystal,H., Fuld,P. and Yen,S.H.,Alzheimer's disease. A double-labeling immunohistochemical study of senile plaques 1, Am. J. Pathol., 132 (1988) 86-101.
[39] Dickson,T.C. and Vickers,J.C, The morphological phenotype of beta-amyloid plaques and associated neuritic changes in Alzheimer's disease 1, Neuroscience, 105(2001)99-107.
[40] Grace,E.A., Rabiner,C.A. and BusciglioJ., Characterization of neuronal dystrophy induced by fibrillar amyloid beta: implications for Alzheimer's disease3,Neuroscience, 114 (2002) 265-273.
[41] Spires,T.L. and Hyman,B.T., Neuronal structure is altered by amyloid plaquesl, Rev. Neurosci., 15 (2004) 267-278.
[42] Hoareau,C, Borrell,V., Soriano,E., Krebs,M.O., Prochiantz,A. and Allinquant,B., Amyloid precursor protein cytoplasmic domain antagonizes reelin neurite outgrowth inhibition of hippocampal neuronsl, Neurobiol. Aging, 29 (2008)542-553.
[43] Maruyama,K., Kumagae,Y., Saito,Y., Yamao-Harigaya,W., Usami,M., Ishiura,S., Kawashima,S. and Obata,K., The toxic effect of Alzheimer amyloid protein precursor overexpressed in the neuroblastoma cell line NB-1 on neurite outgrowth1,Gerontology, 40 Suppl 2 (1994) 57-64.
[44] Yoshikawa,K., Aizawa,T. and Hayashi,Y., Degeneration in vitro of post-mitotic neurons overexpressing the Alzheimer amyloid protein precursor1, Nature,359 (1992) 64-67.
[45] Fein,J.A., Sokolow,S., Miller.CA., Vinters,H.V., Yang,F., Cole,G.M. and Gylys,K.H., Co-localization of amyloid beta and tau pathology in Alzheimer's disease synaptosomes, Am. J. Pathol., 172 (2008) 1683-1692.
[46] Mattson,M.P., Secreted forms of beta-amyloid precursor protein modulate dendrite outgrowth and calcium responses to glutamate in cultured embryonic hippocampal neurons 1, J. Neurobiol., 25 (1994) 439-450.
[47] Teter,B. and Ashford,J.W., Neuroplasticity in Alzheimer's diseasel, J.Neurosci. Res., 70 (2002) 402-437.
[48] Susen,K. and Blochl,A., Low concentrations of aggregated beta-amyloid induce neurite formation via the neurotrophin receptor p75, J. Mol. Med., 83 (2005)720-735.
[49] Iijima,K., Chiang,H.C, Hearn,S.A., Hakker,L, Gatt,A., Shenton,C,Granger,L., Leung,A., Iijima-Ando,K. and Zhong,Y., Abeta42 mutants with different aggregation profiles induce distinct pathologies in Drosophila, PLoS. ONE., 3 (2008)el703.
[50] Masliah,E., Alford,M., Adame,A., Rockenstein,E., Galasko,D., Salmon,D.,Hansen,L.A. and Thal,L.J., Abetal-42 promotes cholinergic sprouting in patients with AD and Lewy body variant of AD, Neurology, 61 (2003) 206-211.
[51] Puttfarcken,P.S., Manelli,A.M., Neilly,J. and Frail,D.E., Inhibition of age-induced beta-amyloid neurotoxicity in rat hippocampal cells, Exp. Neurol., 138(1996)73-81.
[52] Evans,N.A., Facci,L., Owen,D.E., Soden,P.E., Burbidge,S.A., Prinjha,R.K.,Richardson,J.C. and Skaper,S.D., Abeta(1-42) reduces synapse number and inhibits neurite outgrowth in primary cortical and hippocampal neurons: a quantitative analysis1, J. Neurosci. Methods, 175 (2008) 96-103.
[53] Lin,H., Bhatia,R. and Lal,R., Amyloid beta protein forms ion channels:implications for Alzheimer's disease pathophysiology, FASEB J., 15 (2001) 2433-2444.
[54] Abad,M.A., Enguita,M., Gregorio-Rocasolano,N., Ferrer,I. and Trullas,R.,Neuronal pentraxin 1 contributes to the neuronal damage evoked by amyloid-beta and is overexpressed in dystrophic neurites in Alzheimer's brain, J. Neurosci., 26 (2006)12735-12747.
[55] Hu,M., Schurdak,M.E., Puttfarcken,P.S., E1,K.R., Gopalakrishnan,M. and Li,J., High content screen microscopy analysis of A beta 1-42-induced neurite outgrowth reduction in rat primary cortical neurons: neuroprotective effects of alpha 7 neuronal nicotinic acetylcholine receptor ligands, Brain Res., 1151 (2007) 227-235.
[56] Petratos,S., Li,Q.X., George,A.J., Hou,X., Kerr,M.L., Unabia,S.E.,Hatzinisiriou.I., Maksel,D., Aguilar,M.I. and Small,D.H., The beta-amyloid protein of Alzheimer's disease increases neuronal CRMP-2 phosphorylation by a Rho-GTP mechanisml, Brain, 131 (2008)90-108.
[57] Grace,E.A. and Busciglio,J., Aberrant activation of focal adhesion proteins mediates fibrillar amyloid beta-induced neuronal dystrophy, J. Neurosci., 23 (2003)493-502.
[58] Mattson,M.P. and Duan,W., "Apoptotic" biochemical cascades in synaptic compartments: roles in adaptive plasticity and neurodegenerative disorders, J. Neurosci.Res., 58(1999)152-166.
[59] Postuma,R.B., He,W., NunanJ., Beyreuther,K., Masters,C.L., Barrow,C.J.and Small,D.H., Substrate-bound beta-amyloid peptides inhibit cell adhesion and neurite outgrowth in primary neuronal cultures, J. Neurochem., 74 (2000) 1122-1130.
[60] Yankner,B.A., Duffy,L.K. and Kirschner,D.A., Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides, Science, 250(1990)279-282.
[61] Koo,E.H., Park,L. and Selkoe,D.J., Amyloid beta-protein as a substrate interacts with extracellular matrix to promote neurite outgrowth, Proc. Natl. Acad. Sci.U.S. A, 90 (1993) 4748-4752.
[62] Howard,J. and Pilkington,G.J., Antibodies to fibronectin bind to plaques and other structures in Alzheimer's disease and control brain, Neurosci. Lett., 118 (1990)71-76.
[63] Perlmutter,L.S., Barron,E., Saperia,D. and Chui,H.C, Association between vascular basement membrane components and the lesions of Alzheimer's disease, J.Neurosci. Res., 30 (1991) 673-681.
[64] Snow,A.D., Mar,H., Nochlin,D., Kimata,K., Kato,M., Suzuki,S., Hassell,J.and Wight,T.N., The presence of heparan sulfate proteoglycans in the neuritic plaques and congophilic angiopathy in Alzheimer's disease, Am. J. Pathol., 133 (1988) 456-463.
[65] Murtomaki,S., Risteli,J., Risteli,L., Koivisto,U.M, Johansson,S. and Liesi,P., Laminin and its neurite outgrowth-promoting domain in the brain in Alzheimer's disease and Down's syndrome patients, J. Neurosci. Res., 32 (1992) 261-273.
[66] Whitson,J.S., Selkoe,D.J. and Cotman,C.W., Amyloid beta protein enhances the survival of hippocampal neurons in vitro, Science, 243 (1989) 1488-1490.
[67] Masliah,E., Mallory,M., Hansen,L., Alford,M., Albright,T., DeTeresa,R.,Terry,R., Baudier,J. and Saitoh,T., Patterns of aberrant sprouting in Alzheimer's disease,Neuron, 6 (1991) 729-739.
[68] Grace,E.A., Rabiner,C.A. and Busciglio,J., Characterization of neuronal dystrophy induced by fibrillar amyloid beta: implications for Alzheimer's disease,Neuroscience, 114 (2002) 265-273.
[69] Benzing,W.C, Mufson,E.J. and Armstrong,D.M., Alzheimer's disease-like dystrophic neurites characteristically associated with senile plaques are not found within other neurodegenerative diseases unless amyloid beta-protein deposition is present,Brain Res., 606 (1993) 10-18.
[70] Noda-Saita,K., Yoneyama,A., Shitaka,Y., Hirai,Y., Terai,K., Wu,J., Takeda,T.,Hyodo,K., Osakabe,N., Yamaguchi,T. and Okada,M., Quantitative analysis of amyloid plaques in a mouse model of Alzheimer's disease by phase-contrast X-ray computed tomography, Neuroscience, 138 (2006) 1205-1213.
[71] Simakova,O. and Arispe,N.J., The cell-selective neurotoxicity of the Alzheimer's Abeta peptide is determined by surface phosphatidylserine and cytosolic ATP levels. Membrane binding is required for Abeta toxicity, J. Neurosci., 27 (2007)13719-13729.
[72] Tohda,C, Matsumoto,N., Zou,K., Meselhy,M.R. and Komatsu,K.,Abeta(25-35)-induced memory impairment, axonal atrophy, and synaptic loss are ameliorated by Ml, A metabolite of protopanaxadiol-type saponins,Neuropsychopharmacology, 29 (2004) 860-868.
[73] Tohda,C, Tamura,T., Matsuyama,S. and Komatsu,K., Promotion of axonal maturation and prevention of memory loss in mice by extracts of Astragalus mongholicusl, Br. J. Pharmacol., 149 (2006) 532-541.
[74] Kuboyama,T., Tohda,C. and Komatsu,K., Withanoside Ⅳ and its active metabolite, sominone, attenuate Abeta(25-35)-induced neurodegenerationl, Eur. J.Neurosci., 23 (2006) 1417-1426.
[75] Lai,C.S., Yu,M.S., Yuen,W.H., So,K.F., Zee,S.Y. and Chang,R.C,Antagonizing beta-amyloid peptide neurotoxicity of the anti-aging fungus Ganoderma lucidum, Brain Res., 1190 (2008) 215-224.
[76] Xie,Z., Wei,M., Morgan,T.E., Fabrizio,P., Han,D., Finch,C.E. and Longo,V.D., Peroxynitrite mediates neurotoxicity of amyloid beta-peptidel-42- and lipopolysaccharide-activated microglia, J. Neurosci., 22 (2002) 3484-3492.
[77] Casley,C.S., Land,J.M., Sharpe,M.A., Clark,J.B., Duchen,M.R. and Canevari,L., Beta-amyloid fragment 25-35 causes mitochondrial dysfunction in primary cortical neurons, Neurobiol. Dis., 10 (2002) 258-267.
[78]Iizuka,T., Shoji,M., Harigaya,Y., Kawarabayashi,T., Watanabe,M., Kanai,M.and Hirai,S., Amyloid beta-protein ending at Thr43 is a minor component of some diffuse plaques in the Alzheimer's disease brain, but is not found in cerebrovascular amyloidl, Brain Res., 702 (1995) 275-278.
[79] Mak,K., Yang,F., Vinters,H.V., Frautschy,S.A. and Cole,G.M., Polyclonals to beta-amyloid(1-42) identify most plaque and vascular deposits in Alzheimer cortex, but not striatuml, Brain Res., 667 (1994) 138-142.
[80] Coria,F., Moreno,A., Rubio,I., Garcia,M.A., Morato,E. and Mayor,F., Jr., The cellular pathology associated with Alzheimer beta-amyloid deposits in non-demented aged individual, Neuropathol. Appl. Neurobiol., 19 (1993) 261-268.
[81]Dickson,D.W., The pathogenesis of senile plaquesl, J. Neuropathol. Exp.Neurol.,56 (1997) 321-339.
[82] Yankner,B.A., Mechanisms of neuronal degeneration in Alzheimer's diseasel,Neuron, 16(1996)921-932.
[83] Kasa,P., Papp,H., Zombori,J., Mayer,P. and Checler,F., C-terminal fragments of amyloid-beta peptide cause cholinergic axonal degeneration by a toxic effect rather than by physical injury in the nondemented human brainl, Neurochem. Res., 28 (2003)493-498.
[84] Selkoe,D.J., Amyloid beta-protein and the genetics of Alzheimer's disease 3, J. Biol. Chem., 271 (1996) 18295-18298.
[85] Schwab,C, Steele,J.C. and McGeer,P.L., Dystrophic neurites are associated with early stage extracellular neurofibrillary tangles in the parkinsonism-dementia complex of Guaml, Acta Neuropathol., 94 (1997) 486-492.
[86] Knowles,R.B., Gomez-Isla,T. and Hyman,B.T., Abeta associated neuropil changes: correlation with neuronal loss and demential, J. Neuropathol. Exp. Neurol., 57(1998)1122-1130.
[87] Knowles,R.B., Wyart,C, Buldyrev,S.V., Cruz,L., Urbanc,B., Hasselmo,M.E.,Stanley,H.E. and Hyman,B.T., Plaque-induced neurite abnormalities: implications for disruption of neural networks in Alzheimer's disease2, Proc. Natl. Acad. Sci. U. S. A,96 (1999) 5274-5279.
[88] Masliah,E., Sisk,A., Mallory,M. and Games,D., Neurofibrillary pathology in transgenic mice overexpressing V717F beta-amyloid precursor proteinl, J. Neuropathol.Exp. Neurol., 60 (2001) 357-368.
[89] Irizarry,M.C, Soriano,F., McNamara,M., Page,K.J., Schenk,D., Games,D.and Hyman,B.T., Abeta deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mousel, J. Neurosci., 17 (1997) 7053-7059.
[90] Le,R., Cruz,L., Urbanc,B., Knowles,R.B., Hsiao-Ashe,K., Duff,K., Irizarry,M.C., Stanley,H.E. and Hyman,B.T., Plaque-induced abnormalities in neurite geometry in transgenic models of Alzheimer disease: implications for neural system disruptionl, J. Neuropathol. Exp. Neurol., 60 (2001) 753-758.
[91] Games,D., Adams,D., Alessandrini,R., Barbour,R., Berthelette,P., Blackwell,C, Carr,T., Clemens,J., Donaldson,T., Gillespie,F. and ., Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor proteinl, Nature, 373 (1995) 523-527.
[92] Su,J.H., Cummings,B.J. and Cotman,C.W., Identification and distribution of axonal dystrophic neurites in Alzheimer's disease, Brain Res., 625 (1993) 228-237.
[93] Stokin,G.B., Lillo,C, Falzone,T.L., Brusch,R.G., Rockenstein,E., Mount,S.L.,Raman,R., Davies,P., Masliah,E., Williams,D.S. and Goldstein,L.S., Axonopathy and transport deficits early in the pathogenesis of Alzheimer's diseasel, Science, 307 (2005)1282-1288.
[94] Spires,T.L., Meyer-Luehmann,M., Stern,E.A., McLean,P.J., Skoch,J., Nguyen,P.T., Bacskai,B.J. and Hyman,B.T., Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy1, J. Neurosci., 25 (2005) 7278-7287.
[95] Tomidokoro,Y., Harigaya,Y., Matsubara,E., Ikeda,M., Kawarabayashi,T.,Okamoto,K. and Shoji,M., Impaired neurotransmitter systems by Abeta amyloidosis in APPsw transgenic mice overexpressing amyloid beta protein precursorl, Neurosci. Lett.,292(2000)155-158.
[96]Arendt,T., Alzheimer's disease as a disorder of mechanisms underlying structural brain self-organization4, Neuroscience, 102 (2001) 723-765.
[97] Dickson,T.C, King,C.E., McCormack,G.H. and Vickers,J.C, Neurochemical diversity of dystrophic neurites in the early and late stages of Alzheimer's diseasel, Exp.Neurol., 156(1999)100-110.
[98] Masliah,E., Mallory,M., Hansen,L., Alford,M., DeTeresa,R. and Terry,R., An antibody against phosphorylated neurofilaments identifies a subset of damaged association axons in Alzheimer's diseasel, Am. J. Pathol., 142 (1993) 871-882.
[99] King,C.E., Canty,A.J. and Vickers,J.C, Alterations in neurofilaments associated with reactive brain changes and axonal sprouting following acute physical injury to the rat neocortexl, Neuropathol. Appl. Neurobiol., 27 (2001) 115-126.
[100] Holtzman,D.M., Bales,K.R., Tenkova,T., Fagan,A.M, Parsadanian,M.,Sartorius,L.J., Mackey,B., Olney,J., McKeel,D., Wozniak,D. and Paul,S.M.,Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's diseasel, Proc. Natl. Acad. Sci. U. S. A, 97 (2000)2892-2897.
[101] Sasaki,A., Shoji,M., Harigaya,Y., Kawarabayashi,T., Ikeda,M., Naito,M.,Matsubara,E., Abe,K. and Nakazato,Y., Amyloid cored plaques in Tg2576 transgenic mice are characterized by giant plaques, slightly activated microglia, and the lack of paired helical filament-typed, dystrophic neurites1, Virchows Arch., 441 (2002) 358-367.
[102] Tomidokoro,Y., Harigaya,Y., Matsubara,E., Ikeda,M., Kawarabayashi,T.,Shirao,T., Ishiguro,K., Okamoto,K., Younkin,S.G. and Shoji,M., Brain Abeta amyloidosis in APPsw mice induces accumulation of presenilin-1 and taul, J. Pathol.,194(2001)500-506.
[103] Boutajangout,A., Authelet,M., Blanchard,V., Touchet,N., Tremp,G.,Pradier,L. and Brion,J.P., Characterisation of cytoskeletal abnormalities in mice transgenic for wild-type human tau and familial Alzheimer's disease mutants of APP and presenilin-11, Neurobiol. Dis., 15 (2004) 47-60.
[104] Tsai,J., Grutzendler,J., Duff,K. and Gan,W.B., Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches1, Nat.Neurosci., 7 (2004) 1181-1183.
[105] Fiala.J.C, Feinberg,M., Peters,A. and Barbas,H., Mitochondrial degeneration in dystrophic neurites of senile plaques may lead to extracellular deposition of fine filaments 1, Brain Struct. Funct., 212 (2007) 195-207.
[106] Takahashi,R.H., Milner,T.A., Li,F., Nam,E.E., Edgar,M.A., Yamaguchi,H.,Beal,M.F., Xu,H., Greengard,P. and Gouras,G.K., Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology, Am. J.Pathol., 161 (2002) 1869-1879.
[107] Pastorino,L., Sun,A., Lu,P.J., Zhou,X.Z., Balastik,M., Finn,G., Wulf,G.,Lim,J., Li,S.H., Li,X., Xia,W., Nicholson,L.K. and Lu,K.P., The prolyl isomerase Pinl regulates amyloid precursor protein processing and amyloid-beta production, Nature,440 (2006) 528-534.
[108] Geula,C, Mesulam,M.M., Saroff,D.M. and Wu,C.K., Relationship between plaques, tangles, and loss of cortical cholinergic fibers in Alzheimer disease, J.Neuropathol. Exp. Neurol., 57 (1998) 63-75.
[109] Geula,C, Nagykery,N. and Wu,C.K., Amyloid-beta deposits in the cerebral cortex of the aged common marmoset (Callithrix jacchus): incidence and chemical composition, Acta Neuropathol., 103 (2002) 48-58.
[110] Laporte,V., it-Ghezala,G., Volmar,C.H., Ganey,C, Ganey,N., Wood,M. and Mullan,M., CD40 ligation mediates plaque-associated tau phosphorylation in beta-amyloid overproducing micel, Brain Res., 1231 (2008) 132-142.
[111] Fiala,J.C, Mechanisms of amyloid plaque pathogenesisl, Acta Neuropathol.,114(2007)551-571.
[112] Fiala,J.C, Feinberg,M., Peters,A. and Barbas,H., Mitochondrial degeneration in dystrophic neurites of senile plaques may lead to extracellular deposition of fine filamentsl, Brain Struct. Funct, 212 (2007) 195-207.
[113] Meyer-Luehmann,M., Spires-Jones,T.L., Prada,C, Garcia-Alloza,M.,de,C.A., Rozkalne,A., Koenigsknecht-Talboo,J., Holtzman,D.M., Bacskai,B.J. and Hyman,B.T., Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's diseasel, Nature, 451 (2008) 720-724.
[114] Whalen,B.M., Selkoe,D.J. and Hartley,D.M., Small non-fibrillar assemblies of amyloid beta-protein bearing the Arctic mutation induce rapid neuritic degeneration, Neurobiol. Dis., 20 (2005) 254-266.
[115] Brendza,R.P., Bacskai,B.J., Cirrito,J.R., Simmons,K.A., Skoch,J.M.,Klunk,W.E., Mathis,C.A., Bales,K.R., Paul,S.M., Hyman,B.T. and Holtzman,D.M., Anti-Abeta antibody treatment promotes the rapid recovery of amyloid-associated neuritic dystrophy in PDAPP transgenic micel, J. Clin. Invest, 115 (2005) 428-433.
[116] Brunk,U.T. and Terman,A., The mitochondrial-lysosomal axis theory of aging: accumulation of damaged mitochondria as a result of imperfect autophagocytosisl, Eur. J. Biochem., 269 (2002) 1996-2002.
[117] Schenk,D., Barbour,R., Dunn,W., Gordon,G., Grajeda,H., Guido,T., Hu,K.,Huang,J., Johnson-Wood,K., Khan,K., Kholodenko,D., Lee,M., Liao,Z., Lieberburg,I.,Motter,R., Mutter,L., Soriano,F., Shopp,G., Vasquez,N., Vandevert,C, Walker,S.,Wogulis,M., Yednock,T., Games,D. and Seubert,P., Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse2, Nature, 400 (1999)173-177.
[2]盛树力.老年性痴呆及相关疾病.北京:科学技术文献出版社,2006.
[3]Hardy JA,Higgins GA.Alzheimer's disease:the amyloid cascade hypothesis.Science.1992;256(5054):184-185.
[4]Lambert MP,Barlow AK,Chromy BA,Edwards C,Freed R,Liosatos M,Morgan TE,Rozovsky I,Trommer B,Viola KL,Wals P,Zhang C,Finch CE,Krafft GA,Klein WL.Diffusible,nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins.Proc Natl Acad Sci U S A.1998;95(11):6448-6453.
[5]Walsh DM,Klyubin I,Fadeeva JV,Cullen WK,Anwyl R,Wolfe MS,Rowan MJ,Selkoe DJ.Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.Nature.2002;416(6880):535-539.
[6]Walsh DM,Townsend M,Podlisny MB,Shankar GM,Fadeeva JV,El Agnaf O,Hartley DM,Selkoe DJ.Certain inhibitors of synthetic amyloid beta-peptide(Abeta)fibrillogenesis block oligomerization of natural Abeta and thereby rescue long-term potentiation.J Neurosci.2005;25(10):2455-2462.
[7]Ye C,Walsh DM,Selkoe DJ,Hartley DM.Amyloid beta-protein induced electrophysiological changes are dependent on aggregation state:N-methyl-D-aspartate (NMDA) versus non-NMDA receptor/channel activation.Neurosci Lett.2004;366(3):320-325.
[8]Matharu B,Gibson G,Parsons R,Huckerby TN,Moore SA,Cooper LJ,Millichamp R,Allsop D,Austen B.Galantamine inhibits beta-amyloid aggregation and cytotoxicity.J Neurol Sci.2009.
[9]Glenner GG,Wong CW.Alzheimer's disease:initial report of the purification and characterization of a novel cerebrovascular amyloid protein.Biochem Biophys Res Commun.1984;120(3):885-890.
[10]Yankner BA,Dawes LR,Fisher S,Villa-Komaroff L,Oster-Granite ML,Neve RL. Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease. Science. 1989;245(4916):417-420.
[11] Frautschy SA, Baird A, Cole GM. Effects of injected Alzheimer beta-amyloid cores in rat brain. Proc Natl Acad Sci U S A. 1991;88(19):8362-8366.
[12] Pike CJ, Walencewicz AJ, Glabe CG, Cotman CW. In vitro aging of beta-amyloid protein causes peptide aggregation and neurotoxicity. Brain Res.1991;563(1-2):311-314.
[13] Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M,Ashe KH. A specific amyloid-beta protein assembly in the brain impairs memory.Nature. 2006;440(7082):352-357.
[14] Smale G, Nichols NR, Brady DR, Finch CE, Horton WE, Jr. Evidence for apoptotic cell death in Alzheimer's disease. Exp Neurol. 1995;133(2):225-230.
[15] Golde TE. Alzheimer disease therapy: can the amyloid cascade be halted? J Clin Invest.2003;111(1):11-18.
[16] Wu S, Zhou L, Rose M, Xiao X, Graham SH. c-FLIP-L recombinant adeno-associated virus vector infection prevents Fas-mediated but not nerve growth factor withdrawal-mediated cell death in PC12 cells. Brain Res Mol Brain Res.2004;122(1):79-87.
[17] Su JH, Anderson AJ, Cribbs DH, Tu C, Tong L, Kesslack P, Cotman CW. Fas and Fas ligand are associated with neuritic degeneration in the AD brain and participate in beta-amyloid-induced neuronal death. Neurobiol Dis. 2003; 12(3): 182-193.
[18] Vincent I, Rosado M, Davies P. Mitotic mechanisms in Alzheimer's disease? J Cell Biol. 1996;132(3):413-425.
[19] Vincent I, Jicha G, Rosado M, Dickson DW. Aberrant expression of mitotic cdc2/cyclin B1 kinase in degenerating neurons of Alzheimer's disease brain. J Neurosci.1997;17(10):3588-3598.
[20] McShea A, Harris PL, Webster KR, Wahl AF, Smith MA. Abnormal expression of the cell cycle regulators P16 and CDK4 in Alzheimer's disease. Am J Pathol. 1997; 150(6): 1933-1939.
[21] Neve RL, McPhie DL. Dysfunction of amyloid precursor protein signaling in neurons leads to DNA synthesis and apoptosis. Biochim Biophys Acta.2007;1772(4):430-437.
[22] Nagy Z. The dysregulation of the cell cycle and the diagnosis of Alzheimer's disease. Biochim Biophys Acta. 2007;1772(4):402-408.
[23] Meda L, Bernasconi S, Bonaiuto C, Sozzani S, Zhou D, Otvos L, Jr.,Mantovani A, Rossi F, Cassatella MA. Beta-amyloid (25-35) peptide and IFN-gamma synergistically induce the production of the chemotactic cytokine MCP-l/JE in monocytes and microglial cells. J Immunol. 1996;157(3):1213-1218.
[24] Behl C, Davis JB, Lesley R, Schubert D. Hydrogen peroxide mediates amyloid beta protein toxicity. Cell. 1994;77(6):817-827.
[25] Butterfield DA, Hensley K, Harris M, Mattson M, Carney J. beta-Amyloid peptide free radical fragments initiate synaptosomal lipoperoxidation in a sequence-specific fashion: implications to Alzheimer's disease. Biochem Biophys Res Commun. 1994;200(2):710-715.
[26] Cafe C, Torri C, Bertorelli L, Angeretti N, Lucca E, Forloni G, Marzatico F.Oxidative stress after acute and chronic application of beta-amyloid fragment 25-35 in cortical cultures. Neurosci Lett. 1996;203(1):61-65.
[27] Casley CS, Land JM, Sharpe MA, Clark JB, Duchen MR, Canevari L.Beta-amyloid fragment 25-35 causes mitochondrial dysfunction in primary cortical neurons. Neurobiol Dis. 2002;10(3):258-267.
[28] Blass JP. Brain metabolism and brain disease: is metabolic deficiency the proximate cause of Alzheimer dementia? J Neurosci Res. 2001;66(5):851-856.
[29] Yuan J, Yankner BA. Apoptosis in the nervous system. Nature.2000;407(6805):802-809.
[30] Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, Yuan J.Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature. 2000;403(6765):98-103.
[31] Jellinger KA. Cell death mechanisms in neurodegeneration. J Cell Mol Med.2001;5(1):1-17.
[32] Jin Z, El-Deiry WS. Overview of cell death signaling pathways. Cancer Biol Ther.2005;4(2):139-163.
[33] Stefanis L. Caspase-dependent and -independent neuronal death: two distinct pathways to neuronal injury. Neuroscientist. 2005;11(1):50-62.
[34] Huang DC, Strasser A. BH3-Only proteins-essential initiators of apoptotic cell death. Cell. 2000;103(6):839-842.
[35] van Delft MF, Huang DC. How the Bcl-2 family of proteins interact to regulate apoptosis. Cell Res. 2006;16(2):203-213.
[36] Willis SN, Adams JM. Life in the balance: how BH3-only proteins induce apoptosis. Curr Opin Cell Biol. 2005;17(6):617-625.
[37] Puthalakath H, Strasser A. Keeping killers on a tight leash: transcriptional and post-translational control of the pro-apoptotic activity of BH3-only proteins. Cell Death Differ. 2002;9(5):505-512.
[38] Bouillet P, Strasser A. BH3-only proteins - evolutionarily conserved proapoptotic Bcl-2 family members essential for initiating programmed cell death. J Cell Sci. 2002;115(Pt 8):1567-1574.
[39] Precht TA, Phelps RA, Linseman DA, Butts BD, Le SS, Laessig TA, Bouchard RJ, Heidenreich KA. The permeability transition pore triggers Bax translocation to mitochondria during neuronal apoptosis. Cell Death Differ. 2005;12(3):255-265.
[40] Fujimura M, Morita-Fujimura Y, Murakami K, Kawase M, Chan PH. Cytosolic redistribution of cytochrome c after transient focal cerebral ischemia in rats. J Cereb Blood Flow Metab. 1998;18(11):1239-1247.
[41] Janicke RU, Sprengart ML, Wati MR, Porter AG. Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J Biol Chem. 1998;273(16):9357-9360.
[42] Shi Y. Caspase activation, inhibition, and reactivation: a mechanistic view.Protein Sci. 2004;13(8):1979-1987.
[43] Gastard MC, Troncoso JC, Koliatsos VE. Caspase activation in the limbic cortex of subjects with early Alzheimer's disease. Ann Neurol. 2003;54(3):393-398.
[44] Bhat RV, Leonov S, Luthman J, Scott CW, Lee CM. Interactions between GSK3beta and caspase signalling pathways during NGF deprivation induced cell death. J Alzheimers Dis. 2002;4(4):291-301.
[45] Jover T, Tanaka H, Calderone A, Oguro K, Bennett MV, Etgen AM, Zukin RS.Estrogen protects against global ischemia-induced neuronal death and prevents activation of apoptotic signaling cascades in the hippocampal CA1. J Neurosci.2002;22(6):2115-2124.
[46] Nagata S. Fas ligand-induced apoptosis. Annu Rev Genet. 1999;33:29-55.
[47] Mogi M, Harada M, Kondo T, Mizuno Y, Narabayashi H, Riederer P, Nagatsu T. The soluble form of Fas molecule is elevated in parkinsonian brain tissues. Neurosci Lett. 1996;220(3):195-198.
[48] Paschen W. Role of calcium in neuronal cell injury: which subcellular compartment is involved? Brain Res Bull. 2000;53(4):409-413.
[49] Shimoke K, Amano H, Kishi S, Uchida H, Kudo M, Ikeuchi T. Nerve growth factor attenuates endoplasmic reticulum stress-mediated apoptosis via suppression of caspase-12 activity. J Biochem. 2004;135(3):439-446.
[50] Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH.Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration.Nature. 1999;402(6762):615-622.
[51] Lim AC, Qi RZ. Cyclin-dependent kinases in neural development and degeneration. J Alzheimers Dis. 2003;5(4):329-335.
[52] Nguyen MD, Mushynski WE, Julien JP. Cycling at the interface between neurodevelopment and neurodegeneration. Cell Death Differ. 2002;9(12):1294-1306.
[53] Lopes JP, Oliveira CR, Agostinho P. Role of cyclin-dependent kinase 5 in the neurodegenerative process triggered by amyloid-Beta and prion peptides: implications for Alzheimer's disease and prion-related encephalopathies. Cell Mol Neurobiol.2007;27(7):943-957.
[54] Walsh FS, Doherty P. Neural cell adhesion molecules of the immunoglobulin superfamily: role in axon growth and guidance. Annu Rev Cell Dev Biol.1997;13:425-456.
[55] Shapiro L, Colman DR. The diversity of cadherins and implications for a synaptic adhesive code in the CNS. Neuron. 1999;23(3):427-430.
[56] Hynes RO, Lander AD. Contact and adhesive specificities in the associations,migrations, and targeting of cells and axons. Cell. 1992;68(2):303-322.
[57] Goodman CS, Shatz CJ. Developmental mechanisms that generate precise patterns of neuronal connectivity. Cell. 1993;72 Suppl:77-98.
[58] Yoshihara Y, Mori K. Telencephalin: a neuronal area code molecule? Neurosci Res. 1994;21(2):119-124.
[59] Brummendorf T, Rathjen FG. Structure/function relationships of axon-associated adhesion receptors of the immunoglobulin superfamily. Curr Opin Neurobiol. 1996;6(5):584-593.
[60] Sonderegger P, Rathjen FG. Regulation of axonal growth in the vertebrate nervous system by interactions between glycoproteins belonging to two subgroups of the immunoglobulin superfamily. J Cell Biol. 1992;119(6):1387-1394.
[61] Larson RS, Springer TA. Structure and function of leukocyte integrins.Immunol Rev. 1990;114:181-217.
[62] Gahmberg CG. Leukocyte adhesion: CD11/CD18 integrins and intercellular adhesion molecules. Curr Opin Cell Biol. 1997;9(5):643-650.
[63] Gahmberg CG, Tolvanen M, Kotovuori P. Leukocyte adhesion—structure and function of human leukocyte beta2-integrins and their cellular ligands. Eur J Biochem.1997;245(2):215-232.
[64] Yoshihara Y, Oka S, Nemoto Y, Watanabe Y, Nagata S, Kagamiyama H, Mori K. An ICAM-related neuronal glycoprotein, telencephalin, with brain segment-specific expression. Neuron. 1994;12(3):541-553.
[65] Mizuno T, Yoshihara Y, Inazawa J, Kagamiyama H, Mori K. cDNA cloning and chromosomal localization of the human telencephalin and its distinctive interaction with lymphocyte function-associated antigen-1. J Biol Chem. 1997;272(2):1156-1163.
[66] Hayflick JS, Kilgannon P, Gallatin WM. The intercellular adhesion molecule (ICAM) family of proteins. New members and novel functions. Immunol Res.1998;17(3):313-327.
[67] Gahmberg CG, Tian L, Ning L, Nyman-Huttunen H. ICAM-5--a novel two-facetted adhesion molecule in the mammalian brain. Immunol Lett. 2008;117(2):131-135.
[68] Hino H, Mori K, Yoshihara Y, Iseki E, Akiyama H, Nishimura T, Ikeda K,Kosaka K. Reduction of telencephalin immunoreactivity in the brain of patients with Alzheimer's disease. Brain Res. 1997;753(2):353-357.
[69] Rieckmann P, Turner T, Kligannon P, Steinhoff BJ. Telencephalin as an indicator for temporal-lobe dysfunction. Lancet. 1998;352(9125):370-371.
[70] Furutani Y, Matsuno H, Kawasaki M, Sasaki T, Mori K, Yoshihara Y.Interaction between telencephalin and ERM family proteins mediates dendritic filopodia formation. J Neurosci. 2007;27(33):8866-8876.
[71] Gautreau A, Poullet P, Louvard D, Arpin M. Ezrin, a plasma membrane-microfilament linker, signals cell survival through the phosphatidylinositol 3-kinase/Akt pathway. Proc Natl Acad Sci U S A. 1999;96(13):7300-7305.
[72] Mori K, Fujita SC, Watanabe Y, Obata K, Hayaishi O. Telencephalon-specific antigen identified by monoclonal antibody. Proc Natl Acad Sci U S A.1987;84(11):3921-3925.
[73] Oka S, Mori K, Watanabe Y. Mammalian telencephalic neurons express a segment-specific membrane glycoprotein, telencephalin. Neuroscience.1990;35(1):93-103.
[74] Trask B, Fertitta A, Christensen M, Youngblom J, Bergmann A, Copeland A,de Jong P, Mohrenweiser H, Olsen A, Carrano A, et al. Fluorescence in situ hybridization mapping of human chromosome 19: cytogenetic band location of 540 cosmids and 70 genes or DNA markers. Genomics. 1993;15(1):133-145.
[75] Kilgannon P, Turner T, Meyer J, Wisdom W, Gallatin WM. Mapping of the ICAM-5 (telencephalin) gene, a neuronal member of the ICAM family, to a location between ICAM-1 and ICAM-3 on human chromosome 19p13.2. Genomics.1998;54(2):328-330.
[76] Tian L, Yoshihara Y, Mizuno T, Mori K, Gahmberg CG. The neuronal glycoprotein telencephalin is a cellular ligand for the CD1 la/CD 18 leukocyte integrin. J Immunol. 1997;158(2):928-936.
[77] Tian L, Kilgannon P, Yoshihara Y, Mori K, Gallatin WM, Carpen O, Gahmberg CG. Binding of T lymphocytes to hippocampal neurons through ICAM-5 (telencephalin) and characterization of its interaction with the leukocyte integrin CDlla/CD18. Eur J Immunol. 2000;30(3):810-818.
[78] Murakami F, Tada Y, Mori K, Oka S, Katsumaru H. Ultrastructural localization of telencephalin, a telencephalon-specific membrane glycoprotein, in rabbit olfactory bulb. Neurosci Res. 1991;11(2):141-145.
[79] Imamura K, Mori K, Oka S, Watanabe Y. Variations by layers and developmental changes in expression of telencephalin in the visual cortex of cat. Neurosci Lett. 1990;119(1):118-121.
[80] Benson DL, Yoshihara Y, Mori K. Polarized distribution and cell type-specific localization of telencephalin, an intercellular adhesion molecule. J Neurosci Res.1998;52(1):43-53.
[81] Arii N, Mizuguchi M, Mori K, Takashima S. Development of telencephalin in the human cerebrum. Microsc Res Tech. 1999;46(1): 18-23.
[82] Sakurai E, Hashikawa T, Yoshihara Y, Kaneko S, Satoh M, Mori K.Involvement of dendritic adhesion molecule telencephalin in hippocampal long-term potentiation. Neuroreport. 1998;9(5):881-886.
[83] Tamada A, Yoshihara Y, Mori K. Dendrite-associated cell adhesion molecule,telencephalin, promotes neurite outgrowth in mouse embryo. Neurosci Lett.1998;240(3):163-166.
[84] Tian L, Nyman H, Kilgannon P, Yoshihara Y, Mori K, Andersson LC, Kaukinen S, Rauvala H, Gallatin WM, Gahmberg CG. Intercellular adhesion molecule-5 induces dendritic outgrowth by homophilic adhesion. J Cell Biol.2000;150(1):243-252.
[85] Matsuno H, Okabe S, Mishina M, Yanagida T, Mori K, Yoshihara Y.Telencephalin slows spine maturation. J Neurosci. 2006;26(6):1776-1786.
[86] 黄培堂等译. 分子克隆. 北京, 2002.
[87] Chen GJ, Xu J, Lahousse SA, Caggiano NL, de la Monte SM. Transient hypoxia causes Alzheimer-type molecular and biochemical abnormalities in cortical neurons: potential strategies for neuroprotection. J Alzheimers Dis. 2003;5(3):209-228.
[88] Thinakaran G, Borchelt DR, Lee MK, Slunt HH, Spitzer L, Kim G, Ratovitsky T, Davenport F, Nordstedt C, Seeger M, Hardy J, Levey AI, Gandy SE, Jenkins NA,Copeland NG, Price DL, Sisodia SS. Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron. 1996;17(1): 181-190.
[89] Thinakaran G, Harris CL, Ratovitski T, Davenport F, Slunt HH, Price DL,Borchelt DR, Sisodia SS. Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors. J Biol Chem.1997;272(45):28415-28422.
[90] Kim TW, Pettingell WH, Hallmark OG, Moir RD, Wasco W, Tanzi RE.Endoproteolytic cleavage and proteasomal degradation of presenilin 2 in transfected cells. J Biol Chem. 1997;272(17):11006-11010.
[91] Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G,Johnson-Wood K, Lee M, Seubert P, Davis A, Kholodenko D, Motter R, Sherrington R,Perry B, Yao H, Strome R, Lieberburg I, Rommens J, Kim S, Schenk D, Fraser P, St George Hyslop P, Selkoe DJ. Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nat Med. 1997;3(1):67-72.
[92] Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J, Hutton M, Buee L,Harigaya Y, Yager D, Morgan D, Gordon MN, Holcomb L, Refolo L, Zenk B, Hardy J,Younkin S. Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1.Nature. 1996;383(6602):710-713.
[93] Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD,Hardy J, Hutton M, Kukull W, Larson E, Levy-Lahad E, Viitanen M, Peskind E,Poorkaj P, Schellenberg G, Tanzi R, Wasco W, Lannfelt L, Selkoe D, Younkin S. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat Med. 1996;2(8):864-870.
[94] Busciglio J, Lorenzo A, Yankner BA. Methodological variables in the assessment of beta amyloid neurotoxiciry. Neurobiol Aging. 1992;13(5):609-612.
[95] Emre M, Geula C, Ransil BJ, Mesulam MM. The acute neurotoxicity and effects upon cholinergic axons of intracerebrally injected beta-amyloid in the rat brain.Neurobiol Aging. 1992;13(5):553-559.
[96] Kowall NW, Beal MF, Busciglio J, Duffy LK, Yankner BA. An in vivo model for the neurodegenerative effects of beta amyloid and protection by substance P. Proc Natl Acad Sci U S A. 1991;88(16):7247-7251.
[97] Lorenzo A, Yankner BA. Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. Proc Natl Acad Sci U S A. 1994;91(25):12243-12247.
[98] Pike CJ, Walencewicz-Wasserman AJ, Kosmoski J, Cribbs DH, Glabe CG,Cotman CW. Structure-activity analyses of beta-amyloid peptides: contributions of the beta 25-35 region to aggregation and neurotoxicity. J Neurochem. 1995;64(l):253-265.
[99] Maurice T, Su TP, Privat A. Sigmal (sigma 1) receptor agonists and neurosteroids attenuate B25-35-amyloid peptide-induced amnesia in mice through a common mechanism. Neuroscience. 1998;83(2):413-428.
[100] Stepanichev MY, Moiseeva YV, Lazareva NA, Onufriev MV, Gulyaeva NV. Single intracerebroventricular administration of amyloid-beta (25-35) peptide induces impairment in short-term rather than long-term memory in rats. Brain Res Bull.2003;61(2):197-205.
[101] Cheng G, Whitehead SN, Hachinski V, Cechetto DF. Effects of pyrrolidine dithiocarbamate on beta-amyloid (25-35)-induced inflammatory responses and memory deficits in the rat. Neurobiol Dis. 2006;23(l):140-151.
[102] Nie BM, Jiang XY, Cai JX, Fu SL, Yang LM, Lin L, Hang Q, Lu PL, Lu Y. Panaxydol and panaxynol protect cultured cortical neurons against Abeta25-35-induced toxicity. Neuropharmacology. 2008;54(5):845-853.
[103] Mook-Jung I, Joo I, Sohn S, Kwon HJ, Huh K, Jung MW. Estrogen blocks neurotoxic effects of beta-amyloid (1-42) and induces neurite extension on B103 cells.Neurosci Lett. 1997;235(3):101-104.
[104] Puttfarcken PS, Manelli AM, Neilly J, Frail DE. Inhibition of age-induced beta-amyloid neurotoxicity in rat hippocampal cells. Exp Neurol. 1996;138(1):73-81.
[105] Mueller-Steiner S, Zhou Y, Arai H, Roberson ED, Sun B, Chen J, Wang X,Yu G, Esposito L, Mucke L, Gan L. Antiamyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimer's disease. Neuron. 2006;51(6):703-714.
[106] Annaert WG, Esselens C, Baert V, Boeve C, Snellings G, Cupers P,Craessaerts K, De Strooper B. Interaction with telencephalin and the amyloid precursor protein predicts a ring structure for presenilins. Neuron. 2001;32(4):579-589.
[107] Esselens C, Oorschot V, Baert V, Raemaekers T, Spittaels K, Serneels L,Zheng H, Saftig P, De Strooper B, Klumperman J, Annaert W. Presenilin 1 mediates the turnover of telencephalin in hippocampal neurons via an autophagic degradative pathway. J Cell Biol. 2004;166(7):1041-1054.
[108] Pike CJ, Burdick D, Walencewicz AJ, Glabe CG, Cotman CW.Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state. J Neurosci. 1993; 13(4): 1676-1687.
[109] Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR,Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS,Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O'Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W,Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T. Inflammation and Alzheimer's disease.Neurobiol Aging. 2000;21(3):383-421.
[110] LaFerla FM, Green KN, Oddo S. Intracellular amyloid-beta in Alzheimer's disease. Nat Rev Neurosci. 2007;8(7):499-509.
[111] Wegiel J, Kuchna I,Nowicki K, Frackowiak J, Mazur-Kolecka B, Imaki H,Mehta PD, Silverman WP, Reisberg B, Deleon M, Wisniewski T, Pirttilla T, Frey H,Lehtimaki T, Kivimaki T, Visser FE, Kamphorst W, Potempska A, Bolton D, Currie JR,Miller DL. Intraneuronal Abeta immunoreactivity is not a predictor of brain amyloidosis-beta or neurofibrillary degeneration. Acta Neuropathol.2007;113(4):389-402.
[112] Esler WP, Wolfe MS. A portrait of Alzheimer secretases—new features and familiar faces. Science. 2001;293(5534):1449-1454.
[113] Haass C, Selkoe DJ. Cellular processing of beta-amyloid precursor protein and the genesis of amyloid beta-peptide. Cell. 1993;75(6):1039-1042.
[114] Selkoe DJ. The cell biology of beta-amyloid precursor protein and presenilin in Alzheimer's disease. Trends Cell Biol. 1998;8(11):447-453.
[115] Tanzi RE, Moir RD, Wagner SL. Clearance of Alzheimer's Abeta peptide:the many roads to perdition. Neuron. 2004;43(5):605-608.
[116] De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G,Annaert W, Von Figura K, Van Leuven F. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature. 1998;391(6665):387-390.
[117] Li X, Greenwald I. Additional evidence for an eight-transmembrane-domain topology for Caenorhabditis elegans and human presenilins. Proc Natl Acad Sci U S A. 1998;95(12):7109-7114.
[118] Laudon H, Hansson EM, Melen K, Bergman A, Farmery MR, Winblad B,Lendahl U, von Heijne G, Naslund J. A nine-transmembrane domain topology for presenilin 1. J Biol Chem. 2005;280(42):35352-35360.
[119] Henricson A, Kail L, Sonnhammer EL. A novel transmembrane topology of presenilin based on reconciling experimental and computational evidence. FEBS J.2005;272(11):2727-2733.
[120] De Strooper B. Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex. Neuron. 2003;38(l):9-12.
[121] Selkoe DJ, Wolfe MS. Presenilin: running with scissors in the membrane.Cell. 2007; 131(2):215-221.
[122] Annaert W, De Strooper B. A cell biological perspective on Alzheimer's disease. Annu Rev Cell Dev Biol. 2002; 18:25-51.
[123] Selkoe D, Kopan R. Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. Annu Rev Neurosci. 2003;26:565-597.
[124] Annaert W, De Strooper B. Presenilins: molecular switches between proteolysis and signal transduction. Trends Neurosci. 1999;22(10):439-443.
[125] Brown MS, Ye J, Rawson RB, Goldstein JL. Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell.2000;100(4):391-398.
[126] Lindsberg PJ, Launes J, Tian L, Valimaa H, Subramanian V, Siren J, Hokkanen L,Hyypia T,Carpen O,Gahmberg CG.Release of soluble ICAM-5,a neuronal adhesion molecule,in acute encephalitis.Neurology.2002;58(3):446-451.
[127]Petratos S,Li QX,George AJ,Hou X,Kerr ML,Unabia SE,Hatzinisiriou I,Maksel D,Aguilar MI,Small DH.The beta-amyloid protein of Alzheimer's disease increases neuronal CRMP-2 phosphorylation by a Rho-GTP mechanism.Brain.2008;131(Pt 1):90-108.
[128]Lai CS,Yu MS,Yuen WH,So KF,Zee SY,Chang RC.Antagonizing beta-amyloid peptide neurotoxicity of the anti-aging fungus Ganoderma lucidum.Brain Res.2008;1190:215-224.
[129]Hu M,Schurdak ME,Puttfarcken PS,El Kouhen R,Gopalakrishnan M,Li J.High content screen microscopy analysis of A beta 1-42-induced neurite outgrowth reduction in rat primary cortical neurons:neuroprotective effects of alpha 7 neuronal nicotinic acetylcholine receptor ligands.Brain Res.2007;1151:227-235.
[130]Arun P,Madhavarao CN,Moffett JR,Namboodiri MA.Regulation of N-acetylaspartate and N-acetylaspartylglutamate biosynthesis by protein kinase activators.J Neurochem.2006;98(6):2034-2042.
[131]Nyman-Huttunen H,Tian L,Ning L,Gahmberg CG.alpha-Actinin-dependent cytoskeletal anchorage is important for ICAM-5-mediated neuritic outgrowth.J Cell Sci.2006;119(Pt 15):3057-3066.
[132]Masliah E,Alford M,Adame A,Rockenstein E,Galasko D,Salmon D,Hansen LA,Thal LJ.Abetal-42 promotes cholinergic sprouting in patients with AD and Lewy body variant of AD.Neurology.2003;61(2):206-211.
[133]Evans NA,Facci L,Owen DE,Soden PE,Burbidge SA,Prinjha RK,Richardson JC,Skaper SD.Abeta(1-42) reduces synapse number and inhibits neurite outgrowth in primary cortical and hippocampal neurons:a quantitative analysis.J Neurosci Methods.2008;175(1):96-103.
[134]Lin H,Bhatia R,Lal R.Amyloid beta protein forms ion channels:implications for Alzheimer's disease pathophysiology.FASEB J.2001;15(13):2433-2444.
[135]Kuboyama T,Tohda C,Komatsu K.Withanoside IV and its active metabolite, sominone, attenuate Abeta(25-35)-induced neurodegeneration. Eur J Neurosci. 2006;23(6):1417-1426.
[136] Klementiev B, Novikova T, Novitskaya V, Walmod PS, Dmytriyeva O,Pakkenberg B, Berezin V, Bock E. A neural cell adhesion molecule-derived peptide reduces neuropathological signs and cognitive impairment induced by Abeta25-35.Neuroscience. 2007;145(1):209-224.
[137] Tohda C, Matsumoto N, Zou K, Meselhy MR, Komatsu K.Abeta(25-35)-induced memory impairment, axonal atrophy, and synaptic loss are ameliorated by Ml, A metabolite of protopanaxadiol-type saponins.Neuropsychopharmacology. 2004;29(5):860-868.
[138] Tohda C, Ichimura M, Bai Y, Tanaka K, Zhu S, Komatsu K. Inhibitory effects of Eleutherococcus senticosus extracts on amyloid beta(25-35)-induced neuritic atrophy and synaptic loss. J Pharmacol Sci. 2008;107(3):329-339.
[139] Ziv NE, Smith SJ. Evidence for a role of dendritic filopodia in synaptogenesis and spine formation. Neuron. 1996;17(1):91-102.
[140] Fiala JC, Feinberg M, Popov V, Harris KM. Synaptogenesis via dendritic filopodia in developing hippocampal area CA1. J Neurosci. 1998;18(21):8900-8911.
[141] Dailey ME, Smith SJ. The dynamics of dendritic structure in developing hippocampal slices. J Neurosci. 1996;16(9):2983-2994.
[142] Dunaevsky A, Tashiro A, Majewska A, Mason C, Yuste R. Developmental regulation of spine motility in the mammalian central nervous system. Proc Natl Acad Sci U S A. 1999;96(23):13438-13443.
[143] Lendvai B, Stern EA, Chen B, Svoboda K. Experience-dependent plasticity of dendritic spines in the developing rat barrel cortex in vivo. Nature.2000;404(6780):876-881.
[144] Yuste R, Bonhoeffer T. Genesis of dendritic spines: insights from ultrastructural and imaging studies. Nat Rev Neurosci. 2004;5(1):24-34.
[145] Harris KM, Kater SB. Dendritic spines: cellular specializations imparting both stability and flexibility to synaptic function. Annu Rev Neurosci. 1994;17:341-371.
[146] Mitsui S, Saito M, Hayashi K, Mori K, Yoshihara Y. A novel phenylalanine-based targeting signal directs telencephalin to neuronal dendrites.J Neurosci.2005;25(5):1122-1131.
[147]Ferreiro E,Oliveira CR,Pereira CM.The release of calcium from the endoplasmic reticulum induced by amyloid-beta and prion peptides activates the mitochondrial apoptotic pathway.Neurobiol Dis.2008;30(3):331-342.
[148]Lloret A,Badia MC,Mora NJ,Ortega A,Pallardo FV,Alonso MD,Atamna H,Vina J.Gender and age-dependent differences in the mitochondrial apoptogenic pathway in Alzheimer's disease.Free Radic Biol Med.2008;44(12):2019-2025.
[149]Nakamura M,Nakashima S,Katagiri Y,Nozawa Y.Effect of wortmannin and 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one(LY294002) on N-formyl-methionyl-leucyl-phenylalanine-induced phospholipase D activation in differentiated HL60 cells:possible involvement of phosphatidylinositol 3-kinase in phospholipase D activation.Biochem Pharmacol.1997;53(12):1929-1936.
[150]Vlahos CJ,Matter WF,Hui KY,Brown RF.A specific inhibitor of phosphatidylinositol 3-kinase,2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002).J Biol Chem.1994;269(7):5241-5248.
[151]Milosevic I,Sorensen JB,Lang T,Krauss M,Nagy G,Haucke V,Jahn R,Neher E.Plasmalemmal phosphatidylinositol-4,5-bisphosphate level regulates the releasable vesicle pool size in chromaffin cells.J Neurosci.2005;25(10):2557-2565.
[152]Vukic V,Callaghan D,Walker D,Lue LF,Liu QY,Couraud PO,Romero IA,Weksler B,Stanimirovic DB,Zhang W.Expression of inflammatory genes induced by beta-amyloid peptides in human brain endothelial cells and in Alzheimer's brain is mediated by the JNK-AP1 signaling pathway.Neurobiol Dis.2009;34(1):95-106.
[153]Merry DE,Korsmeyer SJ.Bcl-2 gene family in the nervous system.Annu Rev Neurosci.1997;20:245-267.
[154]Zhang Y,McLaughlin R,Goodyer C,LeBlanc A.Selective cytotoxicity of intracellular amyloid beta peptide1-42 through p53 and Bax in cultured primary human neurons.J Cell Biol.2002;156(3):519-529.
[155]Fiala M,Zhang L,Gan X,Sherry B,Taub D,Graves MC,Hama S,Way D, Weinand M, Witte M, Lorton D, Kuo YM, Roher AE. Amyloid-beta induces chemokine secretion and monocyte migration across a human blood—brain barrier model. Mol Med.1998;4(7):480-489.
[156] Mattioli B, Straface E, Quaranta MG, Giordani L, Viora M. Leptin promotes differentiation and survival of human dendritic cells and licenses them for Th1 priming. J Immunol. 2005;174(11):6820-6828.
[157] Gillardon F, Wickert H, Zimmermann M. Up-regulation of bax and down-regulation of bcl-2 is associated with kainate-induced apoptosis in mouse brain.Neurosci Lett. 1995;192(2):85-88.
[158] Grad JM, Zeng XR, Boise LH. Regulation of Bcl-xL: a little bit of this and a little bit of STAT. Curr Opin Oncol. 2000;12(6):543-549.
[159] Sun X, Liu Y, Hu G, Wang H. Protective effects of nicotine against glutamate-induced neurotoxicity in PC12 cells. Cell Mol Biol Lett. 2004;9(3):409-422.
[160] Song YS, Park HJ, Kim SY, Lee SH, Yoo HS, Lee HS, Lee MK, Oh KW,Kang SK, Lee SE, Hong JT. Protective role of Bcl-2 on beta-amyloid-induced cell death of differentiated PC 12 cells: reduction of NF-kappaB and p38 MAP kinase activation.Neurosci Res. 2004;49(1):69-80.
[161] Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES,Wang X. Cytochrome c and dATP-dependent formation of Apaf-l/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997;91(4):479-489.
[162] Marrero MB, Bencherif M. Convergence of alpha 7 nicotinic acetylcholine receptor-activated pathways for anti-apoptosis and anti-inflammation: central role for JAK2 activation of STAT3 and NF-kappaB. Brain Res. 2009;1256:1-7.
[163] Morais Cardoso S, Swerdlow RH, Oliveira CR. Induction of cytochrome c-mediated apoptosis by amyloid beta 25-35 requires functional mitochondria. Brain Res. 2002;931(2):117-125.
[164] Sperandio S, de Belle I, Bredesen DE. An alternative, nonapoptotic form of programmed cell death. Proc Natl Acad Sci U S A. 2000;97(26):14376-14381.
[165] Brunet A, Datta SR, Greenberg ME. Transcription-dependent and-independent control of neuronal survival by the PI3K-Akt signaling pathway. Curr Opin Neurobiol. 2001;11(3):297-305.
[166] Shimoke K, Kishi S, Utsumi T, Shimamura Y, Sasaya H, Oikawa T,Uesato S, Ikeuchi T. NGF-induced phosphatidylinositol 3-kinase signaling pathway prevents thapsigargin-triggered ER stress-mediated apoptosis in PC12 cells. Neurosci Lett.2005;389(3):124-128.
[167] Lee KY, Koh SH, Noh MY, Kim SH, Lee YJ.Phosphatidylinositol-3-kinase activation blocks amyloid beta-induced neurotoxicity.Toxicology. 2008;243(1-2):43-50.
[168] Perez OD, Kinoshita S, Hitoshi Y, Payan DG, Kitamura T, Nolan GP,Lorens JB. Activation of the PKB/AKT pathway by ICAM-2. Immunity.2002;16(1):51-65.
[169] Sakakibara T, Hibi K, Kodera Y, Ito K, Akiyama S, Nakao A.Plasminogen activator inhibitor-1 as a potential marker for the malignancy of esophageal squamous cell carcinoma. Clin Cancer Res. 2004;10(4):1375-1378.
[170] Mitsui S, Saito M, Mori K, Yoshihara Y. A transcriptional enhancer that directs telencephalon-specific transgene expression in mouse brain. Cereb Cortex.2007;17(3):522-530.
[171] Arpin M, Algrain M, Louvard D. Membrane-actin microfilament connections: an increasing diversity of players related to band 4.1. Curr Opin Cell Biol.1994;6(1):136-141.
[172] Bretscher A, Reczek D, Berryman M. Ezrin: a protein requiring conformational activation to link microfilaments to the plasma membrane in the assembly of cell surface structures. J Cell Sci. 1997;110 (Pt 24):3011-3018.
[173] Tsukita S, Yonemura S. ERM proteins: head-to-tail regulation of actin-plasma membrane interaction. Trends Biochem Sci. 1997;22(2):53-58.
[174] Tsukita S, Yonemura S. ERM (ezrin/radixin/moesin) family: from cytoskeleton to signal transduction. Curr Opin Cell Biol. 1997;9(1):70-75.
[175] Vaheri A, Carpen O, Heiska L, Helander TS, Jaaskelainen J,Majander-Nordenswan P, Sainio M, Timonen T, Turunen O. The ezrin protein family:membrane-cytoskeleton interactions and disease associations. Curr Opin Cell Biol. 1997;9(5):659-666.
[176] Bretscher A. Regulation of cortical structure by the ezrin-radixin-moesin protein family. Curr Opin Cell Biol. 1999;11(1):109-116.
[177] Mangeat P, Roy C, Martin M. ERM proteins in cell adhesion and membrane dynamics. Trends Cell Biol. 1999;9(5):187-192.
[178] Tsukita S, Yonemura S. Cortical actin organization: lessons from ERM (ezrin/radixin/moesin) proteins. J Biol Chem. 1999;274(49):34507-34510.
[179] Yonemura S, Nagafuchi A, Sato N, Tsukita S. Concentration of an integral membrane protein, CD43 (leukosialin, sialophorin), in the cleavage furrow through the interaction of its cytoplasmic domain with actin-based cytoskeletons. J Cell Biol.1993;120(2):437-449.
[180] Tsukita S, Oishi K, Sato N, Sagara J, Kawai A. ERM family members as molecular linkers between the cell surface glycoprotein CD44 and actin-based cytoskeletons. J Cell Biol. 1994;126(2):391-401.
[181] Helander TS, Carpen O, Turunen O, Kovanen PE, Vaheri A, Timonen T. ICAM-2 redistributed by ezrin as a target for killer cells. Nature.1996;382(6588):265-268.
[182] Hirao M, Sato N, Kondo T, Yonemura S, Monden M, Sasaki T, Takai Y,Tsukita S. Regulation mechanism of ERM (ezrin/radixin/moesin) protein/plasma membrane association: possible involvement of phosphatidylinositol turnover and Rho-dependent signaling pathway. J Cell Biol. 1996;135(1):37-51.
[183] Yonemura S, Hirao M, Doi Y, Takahashi N, Kondo T, Tsukita S.Ezrin/radixin/moesin (ERM) proteins bind to a positively charged amino acid cluster in the juxta-membrane cytoplasmic domain of CD44, CD43, and ICAM-2. J Cell Biol.1998;140(4):885-895.
[184] Bretscher A, Edwards K, Fehon RG. ERM proteins and merlin: integrators at the cell cortex. Nat Rev Mol Cell Biol. 2002;3(8):586-599.
[185] Turunen O, Wahlstrom T, Vaheri A. Ezrin has a COOH-terminal actin-binding site that is conserved in the ezrin protein family. J Cell Biol.1994;126(6):1445-1453.
[186] Pestonjamasp K, Amieva MR, Strassel CP, Nauseef WM, Furthmayr H,Luna EJ. Moesin, ezrin, and p205 are actin-binding proteins associated with neutrophil plasma membranes. Mol Biol Cell. 1995;6(3):247-259.
[187] Roy C, Martin M, Mangeat P. A dual involvement of the amino-terminal domain of ezrin in F- and G-actin binding. J Biol Chem. 1997;272(32):20088-20095.
[188] Martin M, Roy C, Montcourrier P, Sahuquet A, Mangeat P. Three determinants in ezrin are responsible for cell extension activity. Mol Biol Cell.1997;8(8):1543-1557.
[189] Nakamura F, Amieva MR, Furthmayr H. Phosphorylation of threonine 558 in the carboxyl-terminal actin-binding domain of moesin by thrombin activation of human platelets. J Biol Chem. 1995;270(52):31377-31385.
[190] Hayashi K, Yonemura S, Matsui T, Tsukita S. Immunofluorescence detection of ezrin/radixin/moesin (ERM) proteins with their carboxyl-terminal threonine phosphorylated in cultured cells and tissues. J Cell Sci. 1999;112 (Pt 8):1149-1158.
[191] Stapleton G, Malliri A, Ozanne BW. Downregulated AP-1 activity is associated with inhibition of Protein-Kinase-C-dependent CD44 and ezrin localisation and upregulation of PKC theta in A431 cells. J Cell Sci. 2002; 115(Pt 13):2713-2724.
[192] Martin TA, Harrison G, Mansel RE, Jiang WG. The role of the CD44/ezrin complex in cancer metastasis. Crit Rev Oncol Hematol. 2003;46(2):165-186.
[193] Polesello C, Payre F. Small is beautiful: what flies tell us about ERM protein function in development. Trends Cell Biol. 2004;14(6):294-302.
[194] Kivela T, Jaaskelainen J, Vaheri A, Carpen O. Ezrin, a membrane-organizing protein, as a polarization marker of the retinal pigment epithelium in vertebrates. Cell Tissue Res. 2000;301(2):217-223.
[195] Mangeat P, Roy C, Martin M. ERM proteins in cell adhesion and membrane dynamics: Authors' correction. Trends Cell Biol. 1999;9(7):289.
[196] Matsui T, Maeda M, Doi Y, Yonemura S, Amano M, Kaibuchi K, Tsukita S. Rho-kinase phosphorylates COOH-terminal threonines of ezrin/radixin/moesin (ERM) proteins and regulates their head-to-tail association. J Cell Biol.1998;140(3):647-657.
[197] Gautreau A, Louvard D, Arpin M. Morphogenic effects of ezrin require a phosphorylation-induced transition from oligomers to monomers at the plasma membrane. J Cell Biol. 2000;150(1):193-203.
[198] Otey CA, Carpen 0. Alpha-actinin revisited: a fresh look at an old player.Cell Motil Cytoskeleton. 2004;58(2):104-111.
[199] Cant SH, Pitcher JA. G protein-coupled receptor kinase 2-mediated phosphorylation of ezrin is required for G protein-coupled receptor-dependent reorganization of the actin cytoskeleton. Mol Biol Cell. 2005;16(7):3088-3099.
[200] Papakonstanti EA, Stournaras C. Cell responses regulated by early reorganization of actin cytoskeleton. FEBS Lett. 2008;582(14):2120-2127.
[201] Fievet BT, Gautreau A, Roy C, Del Maestro L, Mangeat P, Louvard D,Arpin M. Phosphoinositide binding and phosphorylation act sequentially in the activation mechanism of ezrin. J Cell Biol. 2004;164(5):653-659.
[202] Khanna C, Wan X, Bose S, Cassaday R, Olomu O, Mendoza A, Yeung C,Gorlick R, Hewitt SM, Helman LJ. The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nat Med. 2004;10(2):182-186.
[203] Yu Y, Khan J, Khanna C, Helman L, Meltzer PS, Merlino G. Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators. Nat Med. 2004;10(2):175-181.
[204] Doi Y, Itoh M, Yonemura S, Ishihara S, Takano H, Noda T, Tsukita S.Normal development of mice and unimpaired cell adhesion/cell motility/actin-based cytoskeleton without compensatory up-regulation of ezrin or radixin in moesin gene knockout. J Biol Chem. 1999;274(4):2315-2321.
[205] Pene F, Claessens YE, Muller O, Viguie F, Mayeux P, Dreyfus F,Lacombe C, Bouscary D. Role of the phosphatidylinositol 3-kinase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apoptosis in multiple myeloma. Oncogene. 2002;21(43):6587-6597.
[206] Corvera S, Czech MP. Direct targets of phosphoinositide 3-kinase products in membrane traffic and signal transduction. Trends Cell Biol. 1998;8(11):442-446.
[207] Coffer PJ, Geijsen N, M'Rabet L, Schweizer RC, Maikoe T, Raaijmakers JA, Lammers JW, Koenderman L. Comparison of the roles of mitogen-activated protein kinase kinase and phosphatidylinositol 3-kinase signal transduction in neutrophil effector function. Biochem J. 1998;329 (Pt 1):121-130.
[208] Coffer PJ, Jin J, Woodgett JR. Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation. Biochem J. 1998;335 (Pt 1):1-13.
[209] Cantley LC. The phosphoinositide 3-kinase pathway. Science.2002;296(5573):1655-1657.
[210] Osaki M, Oshimura M, Ito H. PI3K-Akt pathway: its functions and alterations in human cancer. Apoptosis. 2004;9(6):667-676.
[211] Edwards LA, Thiessen B, Dragowska WH, Daynard T, Bally MB, Dedhar S. Inhibition of ILK in PTEN-mutant human glioblastomas inhibits PKB/Akt activation, induces apoptosis, and delays tumor growth. Oncogene. 2005;24(22):3596-3605.
[212] Song G, Ouyang G, Bao S. The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med. 2005;9(l):59-71.
[213] Huang S, Houghton PJ. Targeting mTOR signaling for cancer therapy.Curr Opin Pharmacol. 2003;3(4):371-377.
[214] Zhou X, Tan M, Stone Hawthorne V, Klos KS, Lan KH, Yang Y, Yang W, Smith TL, Shi D, Yu D. Activation of the Akt/mammalian target of rapamycin/4E-BPl pathway by ErbB2 overexpression predicts tumor progression in breast cancers. Clin Cancer Res. 2004;10(20):6779-6788.
[215] Asnaghi L, Bruno P, Priulla M, Nicolin A. mTOR: a protein kinase switching between life and death. Pharmacol Res. 2004;50(6):545-549.
[216] Schalm SS, Fingar DC, Sabatini DM, Blenis J. TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr Biol.2003;13(10):797-806.
[217] Xu G, Zhang W, Bertram P, Zheng XF, McLeod H. Pharmacogenomic profiling of the PI3K/PTEN-AKT-mTOR pathway in common human tumors. Int J Oncol. 2004;24(4):893-900.
[218] Gao N, Flynn DC, Zhang Z, Zhong XS, Walker V, Liu KJ, Shi X, Jiang BH. Gl cell cycle progression and the expression of Gl cyclins are regulated by PI3K/AKT/mTOR/p70S6Kl signaling in human ovarian cancer cells. Am J Physiol Cell Physiol. 2004;287(2):C281-291.
[219] Franke TF, Hornik CP, Segev L, Shostak GA, Sugimoto C. PI3K/Akt and apoptosis: size matters. Oncogene. 2003;22(56):8983-8998.
[220] Persad S, Dedhar S. The role of integrin-linked kinase (ILK) in cancer progression. Cancer Metastasis Rev. 2003;22(4):375-384.
[221] Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P,Hemmings BA. Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 1996;15(23):6541-6551.
[222] Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts.Genes Dev. 1999;13(22):2905-2927.
[223] Nicholson KM, Anderson NG. The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal. 2002;14(5):381-395.
[224] Takada-Takatori Y, Kume T, Sugimoto M, Katsuki H, Sugimoto H,Akaike A. Acetylcholinesterase inhibitors used in treatment of Alzheimer's disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade. Neuropharmacology. 2006;51(3):474-486.
[225] Gross A, McDonnell JM, Korsmeyer SJ. BCL-2 family members and the mitochondria in apoptosis. Genes Dev. 1999;13(15):1899-1911.
[226] Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME.Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997;91(2):231-241.
[227] del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G.Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science.1997;278(5338):687-689.
[228] Matsuzaki H, Tamatani M, Mitsuda N, Namikawa K, Kiyama H, Miyake S,Tohyama M. Activation of Akt kinase inhibits apoptosis and changes in Bcl-2 and Bax expression induced by nitric oxide in primary hippocampal neurons. J Neurochem.1999;73(5):2037-2046.
[229] Gardai SJ, Hildeman DA, Frankel SK, Whitlock BB, Frasch SC, Borregaard N, Marrack P, Bratton DL, Henson PM. Phosphorylation of Bax Ser184 by Akt regulates its activity and apoptosis in neutrophils. J Biol Chem.2004;279(20):21085-21095.
[230] Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell.1993;74(4):609-619.
[231] Zhang Z, Lapolla SM, Annis MG, Truscott M, Roberts GJ, Miao Y, Shao Y, Tan C, Peng J, Johnson AE, Zhang XC, Andrews DW, Lin J. Bcl-2 homodimerization involves two distinct binding surfaces, a topographic arrangement that provides an effective mechanism for Bcl-2 to capture activated Bax. J Biol Chem.2004;279(42):43920-43928.
[232] Jeong SY, Gaume B, Lee YJ, Hsu YT, Ryu SW, Yoon SH, Youle RJ.Bcl-x(L) sequesters its C-terminal membrane anchor in soluble, cytosolic homodimers.EMBO J. 2004;23(10):2146-2155.
[233] Sadidi M, Lentz SI, Feldman EL. Hydrogen Peroxide-Induced Akt Phosphorylation Regulates Bax Activation. Biochimie. 2009.
[234] Won CK, Ha SJ, Noh HS, Kang SS, Cho GJ, Choi WS, Koh PO. Estradiol prevents the injury-induced decrease of Akt activation and Bad phosphorylation.Neurosci Lett. 2005;387(2):115-119.
[235] Hu Z, Sayeed MM. Activation of PI3-kinase/PKB contributes to delay in neutrophil apoptosis after thermal injury. Am J Physiol Cell Physiol.2005;288(5):C1171-1178.
[236] Xin M, Deng X. Nicotine inactivation of the proapoptotic function of Bax through phosphorylation. J Biol Chem. 2005;280(11):10781-10789.
[237] Mayo LD, Dormer DB. The PTEN, Mdm2, p53 tumor suppressor-oncoprotein network. Trends Biochem Sci. 2002;27(9):462-467.
[238] Wee KB, Aguda BD. Akt versus p53 in a network of oncogenes and tumor suppressor genes regulating cell survival and death. Biophys J. 2006;91(3):857-865.
[239] Gibson EM, Henson ES, Haney N, Villanueva J, Gibson SB. Epidermal growth factor protects epithelial-derived cells from tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by inhibiting cytochrome c release. CancerRes. 2002;62(2):488-496.
[240] Kim EC, Yun BS, Ryoo IJ, Min JK, Won MH, Lee KS, Kim YM, Yoo ID,Kwon YG. Complestatin prevents apoptotic cell death: inhibition of a mitochondrial caspase pathway through AKT/PKB activation. Biochem Biophys Res Commun.2004;313(1):193-204.
[241] Honda K, Shimohama S, Sawada H, Kihara T, Nakamizo T, Shibasaki H,Akaike A. Nongenomic antiapoptotic signal transduction by estrogen in cultured cortical neurons. J Neurosci Res. 2001;64(5):466-475.
[242] Maruya SI, Myers JN, Weber RS, Rosenthal DI, Lotan R, El-Naggar AK.ICAM-5 (telencephalin) gene expression in head and neck squamous carcinoma tumorigenesis and perineural invasion! Oral Oncol. 2005;41(6):580-588.
[243] Delcommenne M, Tan C, Gray V, Rue L, Woodgett J, Dedhar S. Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Proc Natl Acad Sci U S A.1998;95(19):11211-11216.
[244] Walker EH, Pacold ME, Perisic O, Stephens L, Hawkins PT, Wymann MP,Williams RL. Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell.2000;6(4):909-919.
[245] Liu P, Xu B, Li J, Lu H. LY294002 inhibits leukemia cell invasion and migration through early growth response gene 1 induction independent of phosphatidylinositol 3-kinase-Akt pathway. Biochem Biophys Res Commun.2008;377(1):187-190.
[246] Sun H, Xu B, Sheveleva E, Chen QM. LY294002 inhibits glucocorticoid-induced COX-2 gene expression in cardiomyocytes through a phosphatidylinositol 3 kinase-independent mechanism. Toxicol Appl Pharmacol.2008;232(1):25-32.
[247] Poh TW, Pervaiz S. LY294002 and LY303511 sensitize tumor cells to drug-induced apoptosis via intracellular hydrogen peroxide production independent of the phosphoinositide 3-kinase-Akt pathway.Cancer Res.2005;65(14):6264-6274.
[248]Kulik G,Carson JP,Vomastek T,Overman K,Gooch BD,Srinivasula S,Alnemri E,Nunez G,Weber MJ.Tumor necrosis factor alpha induces BID cleavage and bypasses antiapoptotic signals in prostate cancer LNCaP cells.Cancer Res.2001;61(6):2713-2719.
[249]Brognard J,Clark AS,Ni Y,Dennis PA.Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation.Cancer Res.2001;61(10):3986-3997.
[1] Selkoe,D.J., The molecular pathology of Alzheimer's disease, Neuron, 6 (1991)487-498.
[2] Terry,R.D., Masliah,E., Salmon,D.P., Butters,N., DeTeresa,R., Hill,R.,Hansen,L.A. and Katzman,R., Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment, Ann. Neurol., 30(1991) 572-580.
[3] McKee,A.C, Kosik,K.S. and Kowall,N.W., Neuritic pathology and dementia in Alzheimer's disease, Ann. Neurol., 30 (1991) 156-165.
[4] Muresan,Z. and Muresan,V., Neuritic deposits of amyloid-beta peptide in a subpopulation of central nervous system-derived neuronal cells, Mol. Cell Biol., 26(2006) 4982-4997.
[5] Whalen,B.M, Selkoe,D.J. and Hartley,D.M, Small non-fibrillar assemblies of amyloid beta-protein bearing the Arctic mutation induce rapid neuritic degeneration1,Neurobiol. Dis., 20 (2005) 254-266.
[6] Benowitz,L.I., Rodriguez,W., Paskevich,P., Mufson,E.J., Schenk,D. and Neve,R.L., The amyloid precursor protein is concentrated in neuronal lysosomes in normal and Alzheimer disease subjectsl, Exp. Neurol., 106 (1989) 237-250.
[7] McGeer,P.L., Akiyama,H., Kawamata,T., Yamada,T., Walker,D.G. and Ishii,T., Immunohistochemical localization of beta-amyloid precursor protein sequences in Alzheimer and normal brain tissue by light and electron microscopy2, J. Neurosci.Res., 31 (1992) 428-442.
[8] Jung,S.S., Nalbantoglu,J. and Cashman,N.R., Alzheimer's beta-amyloid precursor protein is expressed on the surface of immediately ex vivo brain cells: a flow cytometric studyl, J. Neurosci. Res., 46 (1996) 336-348.
[9] Kang,J., Lemaire,H.G., Unterbeck,A., SalbaumJ.M., Masters,C.L.,Grzeschik,K.H., Multhaup,G., Beyreuther,K. and Muller-Hill,B., The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor1, Nature, 325(1987)733-736.
[10] Selkoe,D.J. and Wolfe,M.S., Presenilin: running with scissors in the membrane1,Cell, 131 (2007)215-221.
[11] Esch,F.S.,Keim,P.S.,Beattie,E.C.,Blacher,R.W.,Culwell,A.R.,Oltersdorf,T.,McClure,D. and Ward,P.J., Cleavage of amyloid beta peptide during constitutive processing of its precursorl, Science, 248 (1990) 1122-1124.
[12] Selkoe,D.J., Cell biology of protein misfolding: the examples of Alzheimer's and Parkinson's diseasesl, Nat. Cell Biol., 6 (2004) 1054-1061.
[13] Wasco,W., Bupp,K., Magendantz,M., GusellaJ.F., Tanzi,R.E. and Solomon,F., Identification of a mouse brain cDNA that encodes a protein related to the Alzheimer disease-associated amyloid beta protein precursorl, Proc. Natl. Acad. Sci. U. S. A, 89(1992) 10758-10762.
[14] Wasco,W., Gurubhagavatula,S., Paradis,M.D., Romano,D.M., Sisodia,S.S.,Hyman,B.T., Neve,R.L. and Tanzi,R.E., Isolation and characterization of APLP2 encoding a homologue of the Alzheimer's associated amyloid beta protein precursor3,Nat. Genet., 5 (1993) 95-100.
[15] Walsh,D.M., FadeevaJ.V., LaVoie,M.J., Paliga,K., Eggert,S., Kimberly,W.T.,Wasco,W. and Selkoe,D.J., gamma-Secretase cleavage and binding to FE65 regulate the nuclear translocation of the intracellular C-terminal domain (ICD) of the APP family of proteinsl, Biochemistry, 42 (2003) 6664-6673.
[16] Scheinfeld,M.H., Ghersi,E., Laky,K., Fowlkes,B.J. and D'Adamio,L.,Processing of beta-amyloid precursor-like protein-1 and -2 by gamma-secretase regulates transcription 1, J. Biol. Chem., 277 (2002) 44195-44201.
[17] Eggert,S., Paliga,K., Soba,P., Evin,G., Masters,C.L., Weidemann,A. and Beyreuther,K., The proteolytic processing of the amyloid precursor protein gene family members APLP-1 and APLP-2 involves alpha-, beta-, gamma-, and epsilon-like cleavages: modulation of APLP-1 processing by n-glycosylationl, J. Biol. Chem., 279(2004) 18146-18156.
[18] Pastorino,L., Ikin,A.F., Lamprianou,S., Vacaresse,N., Revelli,J.P., Platt,K.,Paganetti,P., Mathews,P.M., Harroch,S. and Buxbaum,J.D., BACE (beta-secretase) modulates the processing of APLP2 in vivol, Mol. Cell Neurosci., 25 (2004) 642-649.
[19] Zheng,H., Jiang,M., Trumbauer,M.E., Sirinathsinghji,D.J., Hopkins,R.,Smith,D.W., Heavens,R.P., Dawson,G.R., Boyce,S., Conner,M.W., Stevens,K.A.,Slunt,H.H., Sisoda,S.S., Chen,H.Y. and Van der Ploeg,L.H., beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity1, Cell, 81 (1995)525-531.
[20] Heber,S., Herms,J., Gajic,V., Hainfellner,J., Aguzzi,A., Rulicke,T., von,K.H.,von,K.C, Sisodia,S., Tremml,P., Lipp,H.P., Wolfer,D.P. and Muller.U., Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family membersl, J. Neurosci., 20 (2000) 7951-7963.
[21] Young-Pearse,T.L., Chen,A.C, Chang,R., Marquez,C. and Selkoe,D.J.,Secreted APP regulates the function of full-length APP in neurite outgrowth through interaction with integrin betal 1, Neural Dev., 3 (2008) 15.
[22] Perez,R.G., Zheng,H., Van der Ploeg,L.H. and Koo,E.H., The beta-amyloid precursor protein of Alzheimer's disease enhances neuron viability and modulates neuronal polarityl1, J. Neurosci., 17 (1997) 9407-9414.
[23] Araki,W., Kitaguchi,N., Tokushima,Y., Ishii,K., Aratake,H., Shimohama,S., Nakamura,S. and Kimura,J., Trophic effect of beta-amyloid precursor protein on cerebral cortical neurons in culrure6, Biochem. Biophys. Res. Commun., 181 (1991)265-271.
[24] Ohsawa,I., Hirose,Y., Ishiguro,M, Imai,Y., Ishiura,S. and Kohsaka,S.,Expression, purification, and neurotrophic activity of amyloid precursor protein-secreted forms produced by yeastl, Biochem. Biophys. Res. Commun., 213(1995) 52-58.
[25] Milward,E.A., Papadopoulos,R., Fuller,S.J., Moir,R.D., Small,D., Beyreuther,K. and Masters,C.L., The amyloid protein precursor of Alzheimer's disease is a mediator of the effects of nerve growth factor on neurite outgrowthl, Neuron, 9 (1992)129-137.
[26] Wallace,W.C, Akar,C.A. and Lyons,W.E., Amyloid precursor protein potentiates the neurotrophic activity of NGF3, Brain Res. Mol. Brain Res., 52 (1997)201-212.
[27] Qiu,W.Q., Ferreira,A., Miller,C, Koo,E.H. and Selkoe,D.J., Cell-surface beta-amyloid precursor protein stimulates neurite outgrowth of hippocampal neurons in an isoform-dependent mannerl 1, J. Neurosci., 15 (1995) 2157-2167.
[28] Ando,K., Oishi,M., Takeda,S., Iijima,K., Isohara,T., Nairn,A.C, Kirino,Y.,Greengard,P. and Suzuki,T., Role of phosphorylation of Alzheimer's amyloid precursor protein during neuronal differentiation 1, J. Neurosci., 19 (1999) 4421-4427.
[29] Muresan,Z. and Muresan,V., c-Jun NH2-terminal kinase-interacting protein-3 facilitates phosphorylation and controls localization of amyloid-beta precursor protein2,J. Neurosci., 25 (2005) 3741-3751.
[30] Kibbey,M.C, Jucker,M., Weeks,B.S., Neve,R.L., Van Nostrand,W.E. and Kleinman,H.K., beta-Amyloid precursor protein binds to the neurite-promoting IKVAV site of lamininl, Proc. Natl. Acad. Sci. U. S. A, 90 (1993) 10150-10153.
[31] Annaert,W. and De,S.B., A cell biological perspective on Alzheimer's diseasel, Annu. Rev. Cell Dev. Biol., 18 (2002) 25-51.
[32] Leyssen,M., Ayaz,D., Hebert,S.S., Reeve,S., De,S.B. and Hassan,B.A.,Amyloid precursor protein promotes post-developmental neurite arborization in the Drosophila brainl, EMBO J., 24 (2005) 2944-2955.
[33] Ohsawa,I., Takamura,C. and Kohsaka,S., The amino-terminal region of amyloid precursor protein is responsible for neurite outgrowth in rat neocortical explant culturel, Biochem. Biophys. Res. Commun., 236 (1997) 59-65.
[34] Harper,SJ., Bilsland,J.G., Shearman,M.S., Zheng,H., Van der,P.L. and Sirinathsinghji,D.J., Mouse cortical neurones lacking APP show normal neurite outgrowth and survival responses in vitro2, Neuroreport, 9 (1998) 3053-3058.
[35] Masliah,E., Sisk,A., Mallory,M., Mucke,L., Schenk,D. and Games,D.,Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F beta-amyloid precursor protein and Alzheimer's disease5, J. Neurosci., 16 (1996)5795-5811.
[36] Bodendorf,U., Danner,S., Fischer,F., Stefani,M., Sturchler-Pierrat,C,Wiederhold,K.H., Staufenbiel,M. and Paganetti,P., Expression of human beta-secretase in the mouse brain increases the steady-state level of beta-amyloid2, J. Neurochem., 80 (2002) 799-806.
[37] McKee,A.C, Kosik,K.S. and Kowall,N.W., Neuritic pathology and dementia in Alzheimer's disease1, Ann. Neurol., 30 (1991) 156-165.
[38] Dickson,D.W., Farlo,J., Davies,P., Crystal,H., Fuld,P. and Yen,S.H.,Alzheimer's disease. A double-labeling immunohistochemical study of senile plaques 1, Am. J. Pathol., 132 (1988) 86-101.
[39] Dickson,T.C. and Vickers,J.C, The morphological phenotype of beta-amyloid plaques and associated neuritic changes in Alzheimer's disease 1, Neuroscience, 105(2001)99-107.
[40] Grace,E.A., Rabiner,C.A. and BusciglioJ., Characterization of neuronal dystrophy induced by fibrillar amyloid beta: implications for Alzheimer's disease3,Neuroscience, 114 (2002) 265-273.
[41] Spires,T.L. and Hyman,B.T., Neuronal structure is altered by amyloid plaquesl, Rev. Neurosci., 15 (2004) 267-278.
[42] Hoareau,C, Borrell,V., Soriano,E., Krebs,M.O., Prochiantz,A. and Allinquant,B., Amyloid precursor protein cytoplasmic domain antagonizes reelin neurite outgrowth inhibition of hippocampal neuronsl, Neurobiol. Aging, 29 (2008)542-553.
[43] Maruyama,K., Kumagae,Y., Saito,Y., Yamao-Harigaya,W., Usami,M., Ishiura,S., Kawashima,S. and Obata,K., The toxic effect of Alzheimer amyloid protein precursor overexpressed in the neuroblastoma cell line NB-1 on neurite outgrowth1,Gerontology, 40 Suppl 2 (1994) 57-64.
[44] Yoshikawa,K., Aizawa,T. and Hayashi,Y., Degeneration in vitro of post-mitotic neurons overexpressing the Alzheimer amyloid protein precursor1, Nature,359 (1992) 64-67.
[45] Fein,J.A., Sokolow,S., Miller.CA., Vinters,H.V., Yang,F., Cole,G.M. and Gylys,K.H., Co-localization of amyloid beta and tau pathology in Alzheimer's disease synaptosomes, Am. J. Pathol., 172 (2008) 1683-1692.
[46] Mattson,M.P., Secreted forms of beta-amyloid precursor protein modulate dendrite outgrowth and calcium responses to glutamate in cultured embryonic hippocampal neurons 1, J. Neurobiol., 25 (1994) 439-450.
[47] Teter,B. and Ashford,J.W., Neuroplasticity in Alzheimer's diseasel, J.Neurosci. Res., 70 (2002) 402-437.
[48] Susen,K. and Blochl,A., Low concentrations of aggregated beta-amyloid induce neurite formation via the neurotrophin receptor p75, J. Mol. Med., 83 (2005)720-735.
[49] Iijima,K., Chiang,H.C, Hearn,S.A., Hakker,L, Gatt,A., Shenton,C,Granger,L., Leung,A., Iijima-Ando,K. and Zhong,Y., Abeta42 mutants with different aggregation profiles induce distinct pathologies in Drosophila, PLoS. ONE., 3 (2008)el703.
[50] Masliah,E., Alford,M., Adame,A., Rockenstein,E., Galasko,D., Salmon,D.,Hansen,L.A. and Thal,L.J., Abetal-42 promotes cholinergic sprouting in patients with AD and Lewy body variant of AD, Neurology, 61 (2003) 206-211.
[51] Puttfarcken,P.S., Manelli,A.M., Neilly,J. and Frail,D.E., Inhibition of age-induced beta-amyloid neurotoxicity in rat hippocampal cells, Exp. Neurol., 138(1996)73-81.
[52] Evans,N.A., Facci,L., Owen,D.E., Soden,P.E., Burbidge,S.A., Prinjha,R.K.,Richardson,J.C. and Skaper,S.D., Abeta(1-42) reduces synapse number and inhibits neurite outgrowth in primary cortical and hippocampal neurons: a quantitative analysis1, J. Neurosci. Methods, 175 (2008) 96-103.
[53] Lin,H., Bhatia,R. and Lal,R., Amyloid beta protein forms ion channels:implications for Alzheimer's disease pathophysiology, FASEB J., 15 (2001) 2433-2444.
[54] Abad,M.A., Enguita,M., Gregorio-Rocasolano,N., Ferrer,I. and Trullas,R.,Neuronal pentraxin 1 contributes to the neuronal damage evoked by amyloid-beta and is overexpressed in dystrophic neurites in Alzheimer's brain, J. Neurosci., 26 (2006)12735-12747.
[55] Hu,M., Schurdak,M.E., Puttfarcken,P.S., E1,K.R., Gopalakrishnan,M. and Li,J., High content screen microscopy analysis of A beta 1-42-induced neurite outgrowth reduction in rat primary cortical neurons: neuroprotective effects of alpha 7 neuronal nicotinic acetylcholine receptor ligands, Brain Res., 1151 (2007) 227-235.
[56] Petratos,S., Li,Q.X., George,A.J., Hou,X., Kerr,M.L., Unabia,S.E.,Hatzinisiriou.I., Maksel,D., Aguilar,M.I. and Small,D.H., The beta-amyloid protein of Alzheimer's disease increases neuronal CRMP-2 phosphorylation by a Rho-GTP mechanisml, Brain, 131 (2008)90-108.
[57] Grace,E.A. and Busciglio,J., Aberrant activation of focal adhesion proteins mediates fibrillar amyloid beta-induced neuronal dystrophy, J. Neurosci., 23 (2003)493-502.
[58] Mattson,M.P. and Duan,W., "Apoptotic" biochemical cascades in synaptic compartments: roles in adaptive plasticity and neurodegenerative disorders, J. Neurosci.Res., 58(1999)152-166.
[59] Postuma,R.B., He,W., NunanJ., Beyreuther,K., Masters,C.L., Barrow,C.J.and Small,D.H., Substrate-bound beta-amyloid peptides inhibit cell adhesion and neurite outgrowth in primary neuronal cultures, J. Neurochem., 74 (2000) 1122-1130.
[60] Yankner,B.A., Duffy,L.K. and Kirschner,D.A., Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides, Science, 250(1990)279-282.
[61] Koo,E.H., Park,L. and Selkoe,D.J., Amyloid beta-protein as a substrate interacts with extracellular matrix to promote neurite outgrowth, Proc. Natl. Acad. Sci.U.S. A, 90 (1993) 4748-4752.
[62] Howard,J. and Pilkington,G.J., Antibodies to fibronectin bind to plaques and other structures in Alzheimer's disease and control brain, Neurosci. Lett., 118 (1990)71-76.
[63] Perlmutter,L.S., Barron,E., Saperia,D. and Chui,H.C, Association between vascular basement membrane components and the lesions of Alzheimer's disease, J.Neurosci. Res., 30 (1991) 673-681.
[64] Snow,A.D., Mar,H., Nochlin,D., Kimata,K., Kato,M., Suzuki,S., Hassell,J.and Wight,T.N., The presence of heparan sulfate proteoglycans in the neuritic plaques and congophilic angiopathy in Alzheimer's disease, Am. J. Pathol., 133 (1988) 456-463.
[65] Murtomaki,S., Risteli,J., Risteli,L., Koivisto,U.M, Johansson,S. and Liesi,P., Laminin and its neurite outgrowth-promoting domain in the brain in Alzheimer's disease and Down's syndrome patients, J. Neurosci. Res., 32 (1992) 261-273.
[66] Whitson,J.S., Selkoe,D.J. and Cotman,C.W., Amyloid beta protein enhances the survival of hippocampal neurons in vitro, Science, 243 (1989) 1488-1490.
[67] Masliah,E., Mallory,M., Hansen,L., Alford,M., Albright,T., DeTeresa,R.,Terry,R., Baudier,J. and Saitoh,T., Patterns of aberrant sprouting in Alzheimer's disease,Neuron, 6 (1991) 729-739.
[68] Grace,E.A., Rabiner,C.A. and Busciglio,J., Characterization of neuronal dystrophy induced by fibrillar amyloid beta: implications for Alzheimer's disease,Neuroscience, 114 (2002) 265-273.
[69] Benzing,W.C, Mufson,E.J. and Armstrong,D.M., Alzheimer's disease-like dystrophic neurites characteristically associated with senile plaques are not found within other neurodegenerative diseases unless amyloid beta-protein deposition is present,Brain Res., 606 (1993) 10-18.
[70] Noda-Saita,K., Yoneyama,A., Shitaka,Y., Hirai,Y., Terai,K., Wu,J., Takeda,T.,Hyodo,K., Osakabe,N., Yamaguchi,T. and Okada,M., Quantitative analysis of amyloid plaques in a mouse model of Alzheimer's disease by phase-contrast X-ray computed tomography, Neuroscience, 138 (2006) 1205-1213.
[71] Simakova,O. and Arispe,N.J., The cell-selective neurotoxicity of the Alzheimer's Abeta peptide is determined by surface phosphatidylserine and cytosolic ATP levels. Membrane binding is required for Abeta toxicity, J. Neurosci., 27 (2007)13719-13729.
[72] Tohda,C, Matsumoto,N., Zou,K., Meselhy,M.R. and Komatsu,K.,Abeta(25-35)-induced memory impairment, axonal atrophy, and synaptic loss are ameliorated by Ml, A metabolite of protopanaxadiol-type saponins,Neuropsychopharmacology, 29 (2004) 860-868.
[73] Tohda,C, Tamura,T., Matsuyama,S. and Komatsu,K., Promotion of axonal maturation and prevention of memory loss in mice by extracts of Astragalus mongholicusl, Br. J. Pharmacol., 149 (2006) 532-541.
[74] Kuboyama,T., Tohda,C. and Komatsu,K., Withanoside Ⅳ and its active metabolite, sominone, attenuate Abeta(25-35)-induced neurodegenerationl, Eur. J.Neurosci., 23 (2006) 1417-1426.
[75] Lai,C.S., Yu,M.S., Yuen,W.H., So,K.F., Zee,S.Y. and Chang,R.C,Antagonizing beta-amyloid peptide neurotoxicity of the anti-aging fungus Ganoderma lucidum, Brain Res., 1190 (2008) 215-224.
[76] Xie,Z., Wei,M., Morgan,T.E., Fabrizio,P., Han,D., Finch,C.E. and Longo,V.D., Peroxynitrite mediates neurotoxicity of amyloid beta-peptidel-42- and lipopolysaccharide-activated microglia, J. Neurosci., 22 (2002) 3484-3492.
[77] Casley,C.S., Land,J.M., Sharpe,M.A., Clark,J.B., Duchen,M.R. and Canevari,L., Beta-amyloid fragment 25-35 causes mitochondrial dysfunction in primary cortical neurons, Neurobiol. Dis., 10 (2002) 258-267.
[78]Iizuka,T., Shoji,M., Harigaya,Y., Kawarabayashi,T., Watanabe,M., Kanai,M.and Hirai,S., Amyloid beta-protein ending at Thr43 is a minor component of some diffuse plaques in the Alzheimer's disease brain, but is not found in cerebrovascular amyloidl, Brain Res., 702 (1995) 275-278.
[79] Mak,K., Yang,F., Vinters,H.V., Frautschy,S.A. and Cole,G.M., Polyclonals to beta-amyloid(1-42) identify most plaque and vascular deposits in Alzheimer cortex, but not striatuml, Brain Res., 667 (1994) 138-142.
[80] Coria,F., Moreno,A., Rubio,I., Garcia,M.A., Morato,E. and Mayor,F., Jr., The cellular pathology associated with Alzheimer beta-amyloid deposits in non-demented aged individual, Neuropathol. Appl. Neurobiol., 19 (1993) 261-268.
[81]Dickson,D.W., The pathogenesis of senile plaquesl, J. Neuropathol. Exp.Neurol.,56 (1997) 321-339.
[82] Yankner,B.A., Mechanisms of neuronal degeneration in Alzheimer's diseasel,Neuron, 16(1996)921-932.
[83] Kasa,P., Papp,H., Zombori,J., Mayer,P. and Checler,F., C-terminal fragments of amyloid-beta peptide cause cholinergic axonal degeneration by a toxic effect rather than by physical injury in the nondemented human brainl, Neurochem. Res., 28 (2003)493-498.
[84] Selkoe,D.J., Amyloid beta-protein and the genetics of Alzheimer's disease 3, J. Biol. Chem., 271 (1996) 18295-18298.
[85] Schwab,C, Steele,J.C. and McGeer,P.L., Dystrophic neurites are associated with early stage extracellular neurofibrillary tangles in the parkinsonism-dementia complex of Guaml, Acta Neuropathol., 94 (1997) 486-492.
[86] Knowles,R.B., Gomez-Isla,T. and Hyman,B.T., Abeta associated neuropil changes: correlation with neuronal loss and demential, J. Neuropathol. Exp. Neurol., 57(1998)1122-1130.
[87] Knowles,R.B., Wyart,C, Buldyrev,S.V., Cruz,L., Urbanc,B., Hasselmo,M.E.,Stanley,H.E. and Hyman,B.T., Plaque-induced neurite abnormalities: implications for disruption of neural networks in Alzheimer's disease2, Proc. Natl. Acad. Sci. U. S. A,96 (1999) 5274-5279.
[88] Masliah,E., Sisk,A., Mallory,M. and Games,D., Neurofibrillary pathology in transgenic mice overexpressing V717F beta-amyloid precursor proteinl, J. Neuropathol.Exp. Neurol., 60 (2001) 357-368.
[89] Irizarry,M.C, Soriano,F., McNamara,M., Page,K.J., Schenk,D., Games,D.and Hyman,B.T., Abeta deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mousel, J. Neurosci., 17 (1997) 7053-7059.
[90] Le,R., Cruz,L., Urbanc,B., Knowles,R.B., Hsiao-Ashe,K., Duff,K., Irizarry,M.C., Stanley,H.E. and Hyman,B.T., Plaque-induced abnormalities in neurite geometry in transgenic models of Alzheimer disease: implications for neural system disruptionl, J. Neuropathol. Exp. Neurol., 60 (2001) 753-758.
[91] Games,D., Adams,D., Alessandrini,R., Barbour,R., Berthelette,P., Blackwell,C, Carr,T., Clemens,J., Donaldson,T., Gillespie,F. and ., Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor proteinl, Nature, 373 (1995) 523-527.
[92] Su,J.H., Cummings,B.J. and Cotman,C.W., Identification and distribution of axonal dystrophic neurites in Alzheimer's disease, Brain Res., 625 (1993) 228-237.
[93] Stokin,G.B., Lillo,C, Falzone,T.L., Brusch,R.G., Rockenstein,E., Mount,S.L.,Raman,R., Davies,P., Masliah,E., Williams,D.S. and Goldstein,L.S., Axonopathy and transport deficits early in the pathogenesis of Alzheimer's diseasel, Science, 307 (2005)1282-1288.
[94] Spires,T.L., Meyer-Luehmann,M., Stern,E.A., McLean,P.J., Skoch,J., Nguyen,P.T., Bacskai,B.J. and Hyman,B.T., Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy1, J. Neurosci., 25 (2005) 7278-7287.
[95] Tomidokoro,Y., Harigaya,Y., Matsubara,E., Ikeda,M., Kawarabayashi,T.,Okamoto,K. and Shoji,M., Impaired neurotransmitter systems by Abeta amyloidosis in APPsw transgenic mice overexpressing amyloid beta protein precursorl, Neurosci. Lett.,292(2000)155-158.
[96]Arendt,T., Alzheimer's disease as a disorder of mechanisms underlying structural brain self-organization4, Neuroscience, 102 (2001) 723-765.
[97] Dickson,T.C, King,C.E., McCormack,G.H. and Vickers,J.C, Neurochemical diversity of dystrophic neurites in the early and late stages of Alzheimer's diseasel, Exp.Neurol., 156(1999)100-110.
[98] Masliah,E., Mallory,M., Hansen,L., Alford,M., DeTeresa,R. and Terry,R., An antibody against phosphorylated neurofilaments identifies a subset of damaged association axons in Alzheimer's diseasel, Am. J. Pathol., 142 (1993) 871-882.
[99] King,C.E., Canty,A.J. and Vickers,J.C, Alterations in neurofilaments associated with reactive brain changes and axonal sprouting following acute physical injury to the rat neocortexl, Neuropathol. Appl. Neurobiol., 27 (2001) 115-126.
[100] Holtzman,D.M., Bales,K.R., Tenkova,T., Fagan,A.M, Parsadanian,M.,Sartorius,L.J., Mackey,B., Olney,J., McKeel,D., Wozniak,D. and Paul,S.M.,Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's diseasel, Proc. Natl. Acad. Sci. U. S. A, 97 (2000)2892-2897.
[101] Sasaki,A., Shoji,M., Harigaya,Y., Kawarabayashi,T., Ikeda,M., Naito,M.,Matsubara,E., Abe,K. and Nakazato,Y., Amyloid cored plaques in Tg2576 transgenic mice are characterized by giant plaques, slightly activated microglia, and the lack of paired helical filament-typed, dystrophic neurites1, Virchows Arch., 441 (2002) 358-367.
[102] Tomidokoro,Y., Harigaya,Y., Matsubara,E., Ikeda,M., Kawarabayashi,T.,Shirao,T., Ishiguro,K., Okamoto,K., Younkin,S.G. and Shoji,M., Brain Abeta amyloidosis in APPsw mice induces accumulation of presenilin-1 and taul, J. Pathol.,194(2001)500-506.
[103] Boutajangout,A., Authelet,M., Blanchard,V., Touchet,N., Tremp,G.,Pradier,L. and Brion,J.P., Characterisation of cytoskeletal abnormalities in mice transgenic for wild-type human tau and familial Alzheimer's disease mutants of APP and presenilin-11, Neurobiol. Dis., 15 (2004) 47-60.
[104] Tsai,J., Grutzendler,J., Duff,K. and Gan,W.B., Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches1, Nat.Neurosci., 7 (2004) 1181-1183.
[105] Fiala.J.C, Feinberg,M., Peters,A. and Barbas,H., Mitochondrial degeneration in dystrophic neurites of senile plaques may lead to extracellular deposition of fine filaments 1, Brain Struct. Funct., 212 (2007) 195-207.
[106] Takahashi,R.H., Milner,T.A., Li,F., Nam,E.E., Edgar,M.A., Yamaguchi,H.,Beal,M.F., Xu,H., Greengard,P. and Gouras,G.K., Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology, Am. J.Pathol., 161 (2002) 1869-1879.
[107] Pastorino,L., Sun,A., Lu,P.J., Zhou,X.Z., Balastik,M., Finn,G., Wulf,G.,Lim,J., Li,S.H., Li,X., Xia,W., Nicholson,L.K. and Lu,K.P., The prolyl isomerase Pinl regulates amyloid precursor protein processing and amyloid-beta production, Nature,440 (2006) 528-534.
[108] Geula,C, Mesulam,M.M., Saroff,D.M. and Wu,C.K., Relationship between plaques, tangles, and loss of cortical cholinergic fibers in Alzheimer disease, J.Neuropathol. Exp. Neurol., 57 (1998) 63-75.
[109] Geula,C, Nagykery,N. and Wu,C.K., Amyloid-beta deposits in the cerebral cortex of the aged common marmoset (Callithrix jacchus): incidence and chemical composition, Acta Neuropathol., 103 (2002) 48-58.
[110] Laporte,V., it-Ghezala,G., Volmar,C.H., Ganey,C, Ganey,N., Wood,M. and Mullan,M., CD40 ligation mediates plaque-associated tau phosphorylation in beta-amyloid overproducing micel, Brain Res., 1231 (2008) 132-142.
[111] Fiala,J.C, Mechanisms of amyloid plaque pathogenesisl, Acta Neuropathol.,114(2007)551-571.
[112] Fiala,J.C, Feinberg,M., Peters,A. and Barbas,H., Mitochondrial degeneration in dystrophic neurites of senile plaques may lead to extracellular deposition of fine filamentsl, Brain Struct. Funct, 212 (2007) 195-207.
[113] Meyer-Luehmann,M., Spires-Jones,T.L., Prada,C, Garcia-Alloza,M.,de,C.A., Rozkalne,A., Koenigsknecht-Talboo,J., Holtzman,D.M., Bacskai,B.J. and Hyman,B.T., Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's diseasel, Nature, 451 (2008) 720-724.
[114] Whalen,B.M., Selkoe,D.J. and Hartley,D.M., Small non-fibrillar assemblies of amyloid beta-protein bearing the Arctic mutation induce rapid neuritic degeneration, Neurobiol. Dis., 20 (2005) 254-266.
[115] Brendza,R.P., Bacskai,B.J., Cirrito,J.R., Simmons,K.A., Skoch,J.M.,Klunk,W.E., Mathis,C.A., Bales,K.R., Paul,S.M., Hyman,B.T. and Holtzman,D.M., Anti-Abeta antibody treatment promotes the rapid recovery of amyloid-associated neuritic dystrophy in PDAPP transgenic micel, J. Clin. Invest, 115 (2005) 428-433.
[116] Brunk,U.T. and Terman,A., The mitochondrial-lysosomal axis theory of aging: accumulation of damaged mitochondria as a result of imperfect autophagocytosisl, Eur. J. Biochem., 269 (2002) 1996-2002.
[117] Schenk,D., Barbour,R., Dunn,W., Gordon,G., Grajeda,H., Guido,T., Hu,K.,Huang,J., Johnson-Wood,K., Khan,K., Kholodenko,D., Lee,M., Liao,Z., Lieberburg,I.,Motter,R., Mutter,L., Soriano,F., Shopp,G., Vasquez,N., Vandevert,C, Walker,S.,Wogulis,M., Yednock,T., Games,D. and Seubert,P., Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse2, Nature, 400 (1999)173-177.