NMDA receptor–dependent signaling pathways that underlie amyloid β‐protein disruption of LTP in the hippocampus
NMDA receptor–dependent signaling pathways that underlie amyloid β‐protein disruption of LTP in the hippocampus
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DOI：
10.1002/jnr.21998
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发表时间：
2009-06
影响因子：
4.2
通讯作者：
Ghiam Yamin
中科院分区：
文献类型：
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作者：
Ghiam Yamin
阿尔茨海默病（AD）是老年人群中最常见的神经退行性疾病，其特征在于由淀粉样β蛋白（Aβ）（一种40至42个氨基酸的肽）形成的原纤维的海马沉积。Aβ折叠成神经毒性寡聚体、原纤维和纤维组装体被认为介导了AD的关键病理事件。海马在AD中特别敏感，早期退行性症状包括海马依赖性认知能力（如空间学习和记忆）表现的显著缺陷。表达淀粉样前体蛋白（Aβ的来源蛋白）C末端片段或突变变体的AD转基因小鼠模型显示出年龄依赖性空间记忆障碍和海马CA 1和齿状回（DG）区域的长时程增强（LTP）减弱。最近的实验证据表明，Aβ在体内和体外均干扰CA 1和DG中N-甲基-D-天冬氨酸（NMDA）受体依赖性LTP诱导。此外，这些研究表明，Aβ特异性干扰NMDA受体下游的几种主要信号通路，包括Ca 2+依赖性蛋白磷酸酶钙调磷酸酶、Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMKII）、蛋白磷酸酶1和cAMP反应元件结合蛋白（CREB）。本文综述了Aβ对NMDA受体下游效应子的影响。此外，还简要讨论了LTP调节的其他机制，例如α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体电流的Aβ衰减。© 2009 Wiley利斯公司
Alzheimer's disease (AD), the most common neurodegenerative disease in the elderly population, is characterized by the hippocampal deposition of fibrils formed by amyloid β‐protein (Aβ), a 40‐ to 42‐amino‐acid peptide. The folding of Aβ into neurotoxic oligomeric, protofibrillar, and fibrillar assemblies is believed to mediate the key pathologic event in AD. The hippocampus is especially susceptible in AD and early degenerative symptoms include significant deficits in the performance of hippocampal‐dependent cognitive abilities such as spatial learning and memory. Transgenic mouse models of AD that express C‐terminal segments or mutant variants of amyloid precursor protein, the protein from which Aβ is derived, exhibit age‐dependent spatial memory impairment and attenuated long‐term potentiation (LTP) in the hippocampal CA1 and dentate gyrus (DG) regions. Recent experimental evidence suggests that Aβ disturbs N‐methyl‐D‐aspartic acid (NMDA) receptor–dependent LTP induction in the CA1 and DG both in vivo and in vitro. Furthermore, these studies suggest that Aβ specifically interferes with several major signaling pathways downstream of the NMDA receptor, including the Ca2+‐dependent protein phosphatase calcineurin, Ca2+/calmodulin‐dependent protein kinase II (CaMKII), protein phosphatase 1, and cAMP response element–binding protein (CREB). The influence of Aβ on each of these downstream effectors of the NMDA receptor is reviewed in this article. Additionally, other mechanisms of LTP modulation, such as Aβ attenuation of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor currents, are briefly discussed. © 2009 Wiley‐Liss, Inc.