School of Studies in Biotechnology & Zoology, Vikram University, Ujjain, MP, India.
J Alzheimers Dis. 2010;22(3):741-63. doi: 10.3233/JAD-2010-101020.
Alzheimer's disease is associated with synapse loss, memory dysfunction, and pathological accumulation of amyloid-β (Aβ) in plaques. However, an exclusively pathological role for Aβ is being challenged by new evidence for an essential function of Aβ at the synapse. Aβ protein exists in different assembly states in the central nervous system and plays distinct roles ranging from synapse and memory formation to memory loss and neuronal cell death. Aβ is present in the brain of symptom-free people where it likely performs important physiological roles. New evidence indicates that synaptic activity directly evokes the release of Aβ at the synapse. At physiological levels, Aβ is a normal, soluble product of neuronal metabolism that regulates synaptic function beginning early in life. Monomeric Aβ40 and Aβ42 are the predominant forms required for synaptic plasticity and neuronal survival. With age, some assemblies of Aβ are associated with synaptic failure and Alzheimer's disease pathology, possibly targeting the N-methyl-D-aspartic acid receptor through the nicotinic acetylcholine receptor, mitochondrial Aβ alcohol dehydrogenase, and cyclophilin D. But emerging data suggests a distinction between age effects on the target response in contrast to the assembly state or the accumulation of the peptide. Both aging and Aβ independently decrease neuronal plasticity. Our laboratory has reported that Aβ, glutamate, and lactic acid are each increasingly toxic with neuron age. The basis of the age-related toxicity partly resides in age-related mitochondrial dysfunction and an oxidative shift in mitochondrial and cytoplasmic redox potential. In turn, signaling through phosphorylated extracellular signal-regulated protein kinases is affected along with an age-independent increase in phosphorylated cAMP response element-binding protein. This review examines the long-awaited functional impact of Aβ on synaptic plasticity.
阿尔茨海默病与突触丧失、记忆功能障碍以及淀粉样β（Aβ）在斑块中的病理性积累有关。然而，新的证据表明 Aβ 在突触中具有重要的功能，这对 Aβ 的纯病理性作用提出了挑战。Aβ 蛋白在中枢神经系统中以不同的组装状态存在，并发挥着不同的作用，从突触和记忆形成到记忆丧失和神经元细胞死亡。Aβ 存在于无症状人群的大脑中，在那里它可能发挥着重要的生理作用。新的证据表明，突触活动直接引发 Aβ 在突触中的释放。在生理水平上，Aβ 是神经元代谢的正常可溶性产物，它从生命早期开始调节突触功能。单体 Aβ40 和 Aβ42 是突触可塑性和神经元存活所必需的主要形式。随着年龄的增长，Aβ 的一些组装体与突触功能障碍和阿尔茨海默病病理学有关，可能通过烟碱型乙酰胆碱受体、线粒体 Aβ 醇脱氢酶和亲环蛋白 D 靶向 N-甲基-D-天冬氨酸受体。但新兴数据表明，与肽的组装状态或积累相比，年龄对靶反应的影响存在区别。衰老和 Aβ 都会独立降低神经元的可塑性。我们实验室已经报告说，Aβ、谷氨酸和乳酸随着神经元年龄的增长而变得越来越有毒。与年龄相关的毒性的基础部分在于与年龄相关的线粒体功能障碍以及线粒体和细胞质氧化还原电势的氧化偏移。反过来，通过磷酸化细胞外信号调节蛋白激酶的信号转导以及与年龄无关的磷酸化 cAMP 反应元件结合蛋白的增加也受到影响。这篇综述考察了 Aβ 对突触可塑性的预期已久的功能影响。
