S14G-Humanin拮抗Aβ所致突触可塑性损害及其在AD病程中的神经保护作用和机制研究
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摘要
研究背景和目的:
已有的研究表明,可溶性和纤维性β-淀粉样蛋白(β-amyloid peptide,Aβ)在阿尔茨海默病(Alzheimer’s disease,AD)发病过程中均发挥着至关重要的作用,如何有效地抑制其神经毒性作用已经成为AD治疗的关键问题。Humanin及其衍生物S14G-Humanin(HNG)的发现,为开发AD治疗药物带来了新的希望,但迄今为止,对于其在Aβ所致神经功能损害中的治疗作用及相关机制仍然缺乏深入的研究。本项课题(1)应用小鼠海马脑片,首次从突触可塑性的角度,探讨HNG拮抗Aβ神经毒性的作用及其相关机制;(2)应用转基因AD动物模型(APP/PS-1小鼠),进一步深入探讨HNG在AD病程进展中的治疗作用及其相关机制;为Humanin及其衍生物未来的临床应用提供可靠的实验依据和理论基础。
研究方法:
1.以小鼠海马脑片为研究对象,应用神经电生理技术、免疫组织化学方法和Western blot方法,探讨HNG对于可溶性Aβ所致突触可塑性损害的治疗作用及其相关机制。
2.以转基因AD动物模型(APP/PS-1小鼠)为研究对象,应用多种行为学研究方法、免疫组织化学方法和荧光染色方法,探讨HNG对于AD转基因小鼠行为学障碍的治疗作用及其相关机制。
研究结果:
1.正常对照组、Aβ25-35组、HNG组和Aβ25-35+不同浓度HNG组,随着刺激强度的增加,海马CA1区兴奋性突触后电位(EPSP)波幅和斜率均逐渐增加,在相同刺激强度条件下各个处理组产生的EPSP斜率没有统计学差异(P>0.05)。
2.与正常对照组相比,Aβ25-35组明显抑制海马CA1区早期长时程增强(E-LTP)和晚期长时程增强(L-LTP)的产生(P<0.001),而HNG并不影响海马CA1区E-LTP和L-LTP的产生(P>0.05)。
3.使用不同浓度的HNG(100nM、200nM和400nM)可以不同程度地改善Aβ25-35对海马CA1区E-LTP和L-LTP的抑制作用。与Aβ25-35组相比,HNG 100nM组可以增加E-LTP和L-LTP的产生但并无统计学差异(P>0.05),HNG 200nM组可以明显改善E-LTP和L-LTP的产生(P<0.05),而HNG 400nM组则可以完全逆转Aβ对E-LTP和L-LTP的抑制作用(P<0.001)。
4.在E-LTP中,正常对照组、HNG组、Aβ25-35组和Aβ25-35+ HNG组海马CA1区p-CREB(Ser133)的含量没有明显改变(P>0.05)。在L-LTP中,与正常对照组和HNG组相比,Aβ25-35组海马CA1区p-CREB(Ser133)的含量明显减少(P<0.001);而与Aβ25-35组相比,Aβ25-35+ HNG组海马CA1区p-CREB(Ser133)的含量明显增加(P<0.001)。
5.在Morris水迷宫实验中,与APP/PS-1+生理盐水治疗组相比,APP/PS-1+HNG治疗组能够明显缩短定向航行实验中小鼠找到平台的潜伏期,并明显增加空间探索实验中小鼠在目标象限出现的时间(P<0.05)。在被动回避实验中,与APP/PS-1+生理盐水治疗组相比,APP/PS-1+HNG治疗组能够明显延长小鼠电击刺激后自明箱进入暗箱的潜伏期(P<0.05)。在主动回避实验中,与APP/PS-1+生理盐水治疗组相比,APP/PS-1+HNG治疗组能够明显增加记忆获取实验和记忆保持实验中小鼠的主动回避次数(P<0.05)。
6.与APP/PS-1+生理盐水治疗组海马和大脑皮层Aβ斑块面积相比,APP/PS-1+HNG治疗组海马和大脑皮层Aβ斑块面积没有统计学差异(P>0.05)。与APP/PS-1+生理盐水治疗组海马和大脑皮层纤维性Aβ斑块面积相比,APP/PS-1+HNG治疗组海马和大脑皮层纤维性Aβ斑块面积显著减少(P<0.001)。
研究结论:
1.低浓度的可溶性Aβ通过抑制小鼠海马CA1区E-LTP和L-LTP的产生损害突触可塑性。
2.HNG能够改善可溶性Aβ对于海马CA1区E-LTP和L-LTP的抑制作用,保护突触可塑性,两者之间存在剂量依赖关系。
3.可溶性Aβ对海马CA1区E-LTP的抑制效应及HNG相应的保护作用与p-CREB(Ser133)无关。
4.可溶性Aβ通过减少海马CA1区p-CREB(Ser133)的表达,抑制L-LTP的产生;HNG可以增加p-CREB(Ser133)的含量,改善可溶性Aβ对于海马CA1区L-LTP的抑制作用,发挥突触可塑性保护功能。
5.HNG可以改善APP/PS-1转基因小鼠空间学习记忆功能、伤害性刺激记忆功能和条件反射性学习记忆功能。
6.HNG不影响APP/PS-1小鼠海马和大脑皮层Aβ的数量,但可以抑制纤维性Aβ斑块的形成和沉积。
Background and objective:
Growing evidence has shown that both soluble and fibrillar amyloid-beta peptide (Aβ) play a critical role in the pathogenesis of Alzheimer’s disease (AD). It is now considered to be a key problem that how to inhibit the neurotoxcity of Aβin clinical therapy for the disease. Although the novel neuroprotective agents Humanin and its derivative S14G-Humanin (HNG), have brought new hope for AD therapy, the effect and precise mechanism of HNG on neuroprotection against Aβ-indued dysfunction still remain to be elucidated. In order to better understand the therapeutic potential of Humanin and its derivative for AD, we investigated for the first the neuroprotective effect and mechanism of HNG against Aβ-induced impairment on synaptic plasicity in mouse hippocampal slices, and on congnitive function and Aβexpression in APP/PS-1 transgenic mice.
Methods:
1. By using multi-channel extra-cellular recording system (MED system), immunohistochemistry and Western blot, we investigated the neuroprotective effect and mechanism of HNG against soluble Aβ-induced impairment on synaptic plasticity in mouse hippocampal slices in vitro.
2. By using multiple ethological tests, immunohistochemistry and Thioflavin-S staining, we investigated neuroprotective effect and mechanism of HNG on ethology and Aβexpression in APP/PS-1 transgenic mice in vivo.
Results:
1. Among normal control group, Aβ25-35 group, HNG group and different concentration HNG+Aβ25-35 groups, amplitude and slope of excitatory postsynaptic potential (EPSP) gradually increased with application of increasing stimulus intensity, and no significant changes were found between each group at the same stimulus intensity (P>0.05).
2. Compared with normal control group, both early-phase long-term potentiation (E-LTP) and late-phase long-term potentiation (L-LTP) in hippocampal CA1 region were significantly inhibited by Aβ25-35 (P<0.001), and HNG had no direct influence on the E-LTP and L-LTP induction (P>0.05).
3. Compared with Aβ25-35 group, co-application of 100nM HNG appeared to be a tendency of reducing Aβ25-35-induced E-LTP and L-LTP inhibition, but it did not reach statistic significance (P>0.05). Moreover, co-application of 200nM HNG greatly ameliorated Aβ25-35-induced E-LTP and L-LTP inhibition (P<0.05), and co-application of 400nM HNG completely blocked Aβ25-35-induced E-LTP and L-LTP inhibition (P<0.001).
4. Among normal control group, HNG group, Aβ25-35 group and Aβ25-35+HNG group, no significant differences were found in the level of p-CREB(Ser133) between groups during E-LTP induction (P>0.05). However, when compared with normal control and HNG group, Aβ25-35 induced a significant reduction of p-CREB(Ser133) during L-LTP induction (P<0.001), while the decreased p-CREB(Ser133) was restored by HNG treatment (P<0.001).
5. Morris water maze tests revealed that APP/PS-1+HNG group has significantly shorter escape laterncy in the hidden platform-swimming trails, and significantly more time in the target quadrant in probe trail compared with APP/PS-1+vehicle group (P<0.05). Furthermore, step-through tests showed that APP/PS-1+HNG group has significantly longer laterncy for entering dark chamber after electric shock compared with APP/PS-1+vehicle group (P<0.05), and shuttle-box tests disclosed that APP/PS-1+HNG group has significantly more active avoidance number in acquisition and retention tests as compared with APP/PS-1+vehicle group (P<0.05).
6. As compared with APP/PS-1+vehicle group, APP/PS-1+HNG group appeared to be no significant difference in Aβplaque area in hippocampus and cortex (P>0.05), while significant reduction of fibrilliar Aβplaque area was seen in hippocampus and cortex (P<0.001).
Conclusions:
1. Low-concentration soluble Aβmay cause synaptic plasticity impairment by inhibiting E-LTP and L-LTP induction in hippocampal CA1 region.
2. HNG has a protective role on Aβ-induced synaptic plasticity impairment by reversing the soluble Aβ-induced E-LTP and L-LTP inhibition in hippocampal CA1 region in a dose-dependent manner.
3. p-CREB(Ser133) could not involve in soluble Aβ-induced E-LTP inhibition, or HNG-induced E-LTP protection against Aβin hippocampal CA1 region.
4. Soluble Aβinhibited L-LTP induction through reducing p-CREB(Ser133) level in hippocampal CA1 region, while HNG efficacy for L-LTP protection through restoring p-CREB(Ser133) expression in CA1 region.
5. HNG may ameliorate the dysfunction of spatial learning and memory, insulting stimulus-induced memory, reflexsive learning and memory in APP/PS-1 transgenic mouse.
6. HNG could not reduce the production of Aβ, but could inhibit the formation and deposition of fibrilliar Aβplaque in hippocampus and cortex in APP/PS-1 transgenic mice.
已有的研究表明,可溶性和纤维性β-淀粉样蛋白(β-amyloid peptide,Aβ)在阿尔茨海默病(Alzheimer’s disease,AD)发病过程中均发挥着至关重要的作用,如何有效地抑制其神经毒性作用已经成为AD治疗的关键问题。Humanin及其衍生物S14G-Humanin(HNG)的发现,为开发AD治疗药物带来了新的希望,但迄今为止,对于其在Aβ所致神经功能损害中的治疗作用及相关机制仍然缺乏深入的研究。本项课题(1)应用小鼠海马脑片,首次从突触可塑性的角度,探讨HNG拮抗Aβ神经毒性的作用及其相关机制;(2)应用转基因AD动物模型(APP/PS-1小鼠),进一步深入探讨HNG在AD病程进展中的治疗作用及其相关机制;为Humanin及其衍生物未来的临床应用提供可靠的实验依据和理论基础。
研究方法:
1.以小鼠海马脑片为研究对象,应用神经电生理技术、免疫组织化学方法和Western blot方法,探讨HNG对于可溶性Aβ所致突触可塑性损害的治疗作用及其相关机制。
2.以转基因AD动物模型(APP/PS-1小鼠)为研究对象,应用多种行为学研究方法、免疫组织化学方法和荧光染色方法,探讨HNG对于AD转基因小鼠行为学障碍的治疗作用及其相关机制。
研究结果:
1.正常对照组、Aβ25-35组、HNG组和Aβ25-35+不同浓度HNG组,随着刺激强度的增加,海马CA1区兴奋性突触后电位(EPSP)波幅和斜率均逐渐增加,在相同刺激强度条件下各个处理组产生的EPSP斜率没有统计学差异(P>0.05)。
2.与正常对照组相比,Aβ25-35组明显抑制海马CA1区早期长时程增强(E-LTP)和晚期长时程增强(L-LTP)的产生(P<0.001),而HNG并不影响海马CA1区E-LTP和L-LTP的产生(P>0.05)。
3.使用不同浓度的HNG(100nM、200nM和400nM)可以不同程度地改善Aβ25-35对海马CA1区E-LTP和L-LTP的抑制作用。与Aβ25-35组相比,HNG 100nM组可以增加E-LTP和L-LTP的产生但并无统计学差异(P>0.05),HNG 200nM组可以明显改善E-LTP和L-LTP的产生(P<0.05),而HNG 400nM组则可以完全逆转Aβ对E-LTP和L-LTP的抑制作用(P<0.001)。
4.在E-LTP中,正常对照组、HNG组、Aβ25-35组和Aβ25-35+ HNG组海马CA1区p-CREB(Ser133)的含量没有明显改变(P>0.05)。在L-LTP中,与正常对照组和HNG组相比,Aβ25-35组海马CA1区p-CREB(Ser133)的含量明显减少(P<0.001);而与Aβ25-35组相比,Aβ25-35+ HNG组海马CA1区p-CREB(Ser133)的含量明显增加(P<0.001)。
5.在Morris水迷宫实验中,与APP/PS-1+生理盐水治疗组相比,APP/PS-1+HNG治疗组能够明显缩短定向航行实验中小鼠找到平台的潜伏期,并明显增加空间探索实验中小鼠在目标象限出现的时间(P<0.05)。在被动回避实验中,与APP/PS-1+生理盐水治疗组相比,APP/PS-1+HNG治疗组能够明显延长小鼠电击刺激后自明箱进入暗箱的潜伏期(P<0.05)。在主动回避实验中,与APP/PS-1+生理盐水治疗组相比,APP/PS-1+HNG治疗组能够明显增加记忆获取实验和记忆保持实验中小鼠的主动回避次数(P<0.05)。
6.与APP/PS-1+生理盐水治疗组海马和大脑皮层Aβ斑块面积相比,APP/PS-1+HNG治疗组海马和大脑皮层Aβ斑块面积没有统计学差异(P>0.05)。与APP/PS-1+生理盐水治疗组海马和大脑皮层纤维性Aβ斑块面积相比,APP/PS-1+HNG治疗组海马和大脑皮层纤维性Aβ斑块面积显著减少(P<0.001)。
研究结论:
1.低浓度的可溶性Aβ通过抑制小鼠海马CA1区E-LTP和L-LTP的产生损害突触可塑性。
2.HNG能够改善可溶性Aβ对于海马CA1区E-LTP和L-LTP的抑制作用,保护突触可塑性,两者之间存在剂量依赖关系。
3.可溶性Aβ对海马CA1区E-LTP的抑制效应及HNG相应的保护作用与p-CREB(Ser133)无关。
4.可溶性Aβ通过减少海马CA1区p-CREB(Ser133)的表达,抑制L-LTP的产生;HNG可以增加p-CREB(Ser133)的含量,改善可溶性Aβ对于海马CA1区L-LTP的抑制作用,发挥突触可塑性保护功能。
5.HNG可以改善APP/PS-1转基因小鼠空间学习记忆功能、伤害性刺激记忆功能和条件反射性学习记忆功能。
6.HNG不影响APP/PS-1小鼠海马和大脑皮层Aβ的数量,但可以抑制纤维性Aβ斑块的形成和沉积。
Background and objective:
Growing evidence has shown that both soluble and fibrillar amyloid-beta peptide (Aβ) play a critical role in the pathogenesis of Alzheimer’s disease (AD). It is now considered to be a key problem that how to inhibit the neurotoxcity of Aβin clinical therapy for the disease. Although the novel neuroprotective agents Humanin and its derivative S14G-Humanin (HNG), have brought new hope for AD therapy, the effect and precise mechanism of HNG on neuroprotection against Aβ-indued dysfunction still remain to be elucidated. In order to better understand the therapeutic potential of Humanin and its derivative for AD, we investigated for the first the neuroprotective effect and mechanism of HNG against Aβ-induced impairment on synaptic plasicity in mouse hippocampal slices, and on congnitive function and Aβexpression in APP/PS-1 transgenic mice.
Methods:
1. By using multi-channel extra-cellular recording system (MED system), immunohistochemistry and Western blot, we investigated the neuroprotective effect and mechanism of HNG against soluble Aβ-induced impairment on synaptic plasticity in mouse hippocampal slices in vitro.
2. By using multiple ethological tests, immunohistochemistry and Thioflavin-S staining, we investigated neuroprotective effect and mechanism of HNG on ethology and Aβexpression in APP/PS-1 transgenic mice in vivo.
Results:
1. Among normal control group, Aβ25-35 group, HNG group and different concentration HNG+Aβ25-35 groups, amplitude and slope of excitatory postsynaptic potential (EPSP) gradually increased with application of increasing stimulus intensity, and no significant changes were found between each group at the same stimulus intensity (P>0.05).
2. Compared with normal control group, both early-phase long-term potentiation (E-LTP) and late-phase long-term potentiation (L-LTP) in hippocampal CA1 region were significantly inhibited by Aβ25-35 (P<0.001), and HNG had no direct influence on the E-LTP and L-LTP induction (P>0.05).
3. Compared with Aβ25-35 group, co-application of 100nM HNG appeared to be a tendency of reducing Aβ25-35-induced E-LTP and L-LTP inhibition, but it did not reach statistic significance (P>0.05). Moreover, co-application of 200nM HNG greatly ameliorated Aβ25-35-induced E-LTP and L-LTP inhibition (P<0.05), and co-application of 400nM HNG completely blocked Aβ25-35-induced E-LTP and L-LTP inhibition (P<0.001).
4. Among normal control group, HNG group, Aβ25-35 group and Aβ25-35+HNG group, no significant differences were found in the level of p-CREB(Ser133) between groups during E-LTP induction (P>0.05). However, when compared with normal control and HNG group, Aβ25-35 induced a significant reduction of p-CREB(Ser133) during L-LTP induction (P<0.001), while the decreased p-CREB(Ser133) was restored by HNG treatment (P<0.001).
5. Morris water maze tests revealed that APP/PS-1+HNG group has significantly shorter escape laterncy in the hidden platform-swimming trails, and significantly more time in the target quadrant in probe trail compared with APP/PS-1+vehicle group (P<0.05). Furthermore, step-through tests showed that APP/PS-1+HNG group has significantly longer laterncy for entering dark chamber after electric shock compared with APP/PS-1+vehicle group (P<0.05), and shuttle-box tests disclosed that APP/PS-1+HNG group has significantly more active avoidance number in acquisition and retention tests as compared with APP/PS-1+vehicle group (P<0.05).
6. As compared with APP/PS-1+vehicle group, APP/PS-1+HNG group appeared to be no significant difference in Aβplaque area in hippocampus and cortex (P>0.05), while significant reduction of fibrilliar Aβplaque area was seen in hippocampus and cortex (P<0.001).
Conclusions:
1. Low-concentration soluble Aβmay cause synaptic plasticity impairment by inhibiting E-LTP and L-LTP induction in hippocampal CA1 region.
2. HNG has a protective role on Aβ-induced synaptic plasticity impairment by reversing the soluble Aβ-induced E-LTP and L-LTP inhibition in hippocampal CA1 region in a dose-dependent manner.
3. p-CREB(Ser133) could not involve in soluble Aβ-induced E-LTP inhibition, or HNG-induced E-LTP protection against Aβin hippocampal CA1 region.
4. Soluble Aβinhibited L-LTP induction through reducing p-CREB(Ser133) level in hippocampal CA1 region, while HNG efficacy for L-LTP protection through restoring p-CREB(Ser133) expression in CA1 region.
5. HNG may ameliorate the dysfunction of spatial learning and memory, insulting stimulus-induced memory, reflexsive learning and memory in APP/PS-1 transgenic mouse.
6. HNG could not reduce the production of Aβ, but could inhibit the formation and deposition of fibrilliar Aβplaque in hippocampus and cortex in APP/PS-1 transgenic mice.
引文
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Jung SS, Van Nostrand WE. Humanin rescues human cerebrovascular smoothmuscle cells from Abeta-induced toxicity. J Neurochem, 2003, 84:266-272.
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Ikonen M, Liu B, Hashimoto Y, et a1. Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis. Proc Natl Aead Sci USA, 2003, 100:13042-13047.
Itoh A, Akaike T, Sokabe M, et al. Impairment of long-term potentiation in hippocampal slices ofβ-amyloid-infused rats. Eur J Pharmacol, 1999, 3:167-175.
Jang JH, SurhYJ. Beta-amyloid-induced apoptosis is associated with cyclooxygenase-2 up-regulation via the mitogen-actived protein kinase –NF-kappaB signaling pathway. Free Radic Biol Med, 2005, 38:1604-1613.
Jankowsky JL, Fadale DJ, Anderson J, et al. Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet, 2004, 13:159-170.
Jung SS, Van Nostrand WE. Humanin rescues human cerebrovascular smoothmuscle cells from Abeta-induced toxicity. J Neurochem, 2003, 84:266-272.
Kim JH, Rah JC, Fraser SP, et al. Carboxyl-terminal peptide of beta-amyloid precursor protein blocks inositol 1,4,5-trisphosphate-sensitive Ca2+ release in Xenopus laevis oocytes. J Biol Chem, 2002, 277:20256-20263.
Kovács KA, Steullet P, Steinmann M, et al. TORC1 is a calcium- and cAMP-sensitive coincidence detector involved in hippocampal long-term synaptic plasticity. Proc Natl Acad Sci U S A, 2007, 104:4700-4705.
Krejcova G, Patocka J, Slaninova J. Effect of humanin analogues on experimentally induced impairment of spatial memory in rats. J Pept Sci, 2004, 10:636-639.
Kumar-Singh S, Dewachter I, Moechars D, et al. Behavioral disturbances without amyloid deposits in mice overexpressing human amyloid precursor protein with Flemish (A692G) or Dutch (E693Q) mutation. Neurobiol Dis, 2000, 7:9-22.
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Lue LF, Kuo JH, Roher AE, et al. Soluble amyloidβpeptide concentration as a predictor of synaptic change in Alzheimer’s disease. Am J Pathol, 1999, 155:853-862.
Mamiya T, Ukai M. [Gly14]-Humanin improved the learning and memory impairment induced by scopolamine in vivo. Br J Pharmacol, 2001, 134:1597-1599.
Matsuzaki K, Yamakuni T, Hashimoto M, et al. Nobiletin restoring beta-amyloid-impaired CREB phosphorylation rescues memory deterioretion in Alzheimer’s disease model rats. Neurosci Lett, 2006, 400:2230-2234.
Merry DE. Bcl 22 gene family in the nervous system. Annu Rev Neurosci, 1997, 20:245-267.
Miao J, Zhang W, Yin R, et al. S14G-Humanin ameliorates Abeta25-35-inducedbehavioral deficits by reducing neuroinflammatory responses and apoptosis in mice. Neuropeptides, 2008, 42:557-67.
Minghetti L, Ajmone-CatMA, De BerardinisMA, et al. Microglial activation in chronic neurodegenerative diseases: roles of apoptotic neurons and chronic stimulation. Brain Res Rev, 2005, 48:251-256.
Minogue AM, Schmid AW, Fogarty MP, et al. Activation of the c-Jun N-terminal kinase signaling cascade mediates the effect of amyloid-beta on long term potentiation and cell death in hippocampus: a role for interleukin-1beta? J Biol Chem, 2003, 278:27971-27980.
Miyamoto E. Molecular mechanism of neuronal plasticity: induction and maintenance of long-term potentiation in the hippocampus. J Pharmacol Sci, 2006, 100:433-442.
Moechars D, Dewachter I, Lorent K, et al. Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain. J Biol Chem, 1999, 274:6483-6492.
Morris RGM, Moser EI, Riedel G, et al. Elements of a neurobiological theory of the hippocampus: the role of activity-dependent synaptic plasticity in memory. Philos Trans R Soc Lond B Biol Sci, 2003, 358: 773-786.
Nagele RG, D’Andrea MR, Lee H, et al. Astrocytes accumulate A beta 42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains. Brain Res, 2003, 971:197-209.
Nakagami Y, Oda T. Glutamate exacerbates amyloidβ1-42-induced impairment of long-term potentiation in rat hippocampal slices. Jpn J Pharmacol, 2002, 88:223-226.
Niikura T, Hashimoto Y, Tajima H, et a1. Death and survival of neuronal cells exposed to Alzheimer’s insults. J Neurosci Res, 2002, 70:380-391.
Niikura Y, Abe K, Misawa M. Involvement of L-type Ca2+ channels in the induction of long-term potentiation in the basolateral amygdala-dentate gyrus pathway of anesthetized rats. Brain Res, 2004, 1017:218-221.
Nishimoto I, Matsuoka M, Niikura T. Unravelling the role of Humanin. Trends Mol Med, 2004, 10:102-105.
Oka H, Shimono K, Ogawa R, et al. A new planar multielectrode array for extracellular recording: application to hippocampal acute slice. J Neurosci Methods, 1999, 93:61-67.
Paradis E, Douilard H, Koutroumanis M, et al. Amyloid beta peptide of Alzheimer’s disease downregulates Bcl-2 and upregulates Bax expression in human neurons. J Neurosci, 1996, 16:7533-7539.
Patenaude C, Chapman CA, Bertrand S, et al. GABAB receptor- and metabotropic glutamate receptor-dependent cooperative long-term potentiation of rat hippocampal GABAA synaptic transmission. J Physiol, 2003, 553:155-167.
Qi JS, Qiao JT. Amyloid beta-protein fragment 31-35 forms ion channels in membrane patches excised from rat hippocampal neurons. Neuroscience, 2001, 105:845-852.
Roberson ED, Mucke L.100 years and counting: prospects for defeating Alzheimer disease. Science, 2006, 314:781-784.
Rojo DA, Ramirez GG, Havel J, et al. Structural p references of neuroprotective S14G-humanin peptide analyzed by molecular modeling and circular dichroism. Protein Pept Lett, 2007, 14: 618-624.
Rowan MJ, Klyubin I, Cullen WK, et al. Synaptic plasticity in animal models of early Alzheimer's disease. Philos Trans R Soc Lond B Biol Sci, 2003, 358:821-828.
Rowan MJ, Klyubin I, Wang Q, et al. Mechanisms of the inhibitory effects of amyloid beta-protein on synaptic plasticity. Exp Gerontol, 2004, 39:1661-1667.
Selkoe DJ. Alzheimer disease is a synaptic failure. Science, 2002, 298:789-791.
Tajima H, Kawasumi M, Chiba T, et a1. A humanin derivative, SGly14-Humanin, prevents amyloid-beta-induced memory impairment in mice. J Neurosci Res, 2005, 79:714—723.
Tanzi RE, Bertram L. Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective. Cell, 2005, 120:545-555.
Tauima H, Kawasumi M, Chiba T, et a1. A humanin derivative ,SGly14-Humanin, prevents amyloid-beta-induced memory impairment in mice. J Neurosci Res, 2005, 79:714-723.
Terashita K, Hashimoto Y, Niikura T, et a1. Two serine residues distinctly regulate the rescue function of Humanin, potentiation by isomerization and dimerization.J Neuroehem, 2003, 85:1521-1538.
Tikka T, Fiebich B, Goldsteins G, et al. Minocycline, a tetracycline derivative, is neuroprotective against excitiotoxicity by inhibiting activating and roliferation of microglia. J Neurosci, 2001,21:2580-2588.
Tong L, Thomton PL, Balazs R, et al.β-Amyloid-(1-42) impairs activity-dependent camp-response element-binding protein signaling in neurons at concentrations in which cell survaval is not compromised. J Biol Chem, 2001, 276:17301-17306.
Trommer BL, Shah C, Yun SH, et al. ApoE isoform-specific effects on LTP:blockade by oligomeric amyloid-beta1-42. Neurobiol Dis, 2005, 18:75-82. Vertes RP. Hippocampal theta rhythm: a tag for short-term memory. Hippocampus, 2005, 15:923-35.
Vitolo O, Gong B, Cao Z, et al. Protection against beta-amyloid induced abnormal synaptic function and cell death by Ginkgolide. J. Neurobiol Aging, 2009,30:257-265.
Vitolo OV, Sant’Angelo A, Costanzo V, et al. Amyloidβ-peptide inhibition of the PKA/CREB pathway and long-term potentiation: reversibility by drugs that enhance camp signaling. Proc Natl Acad Sci USA, 2002, 99:13217-13221.
Walsh DM, Klyubuin I, Fadeeva J, et al. Naturally secreted oligomers of the Alzheimer amyloidβ-protein potently inhibit long-term potentiation in vivo. Nature, 2002, 416:535-539.
Wang HW. Soluble oligomers ofβ- amyloid 1-42 inhibit long-term potentiation but not long-term depression in rat dentate gyrus. Brain Res, 2002, 924:133-140.、
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