Li Shaomin, Stern Andrew M
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, 02115, United States.
Mol Psychiatry. 2022 Aug;27(8):3182-3191. doi: 10.1038/s41380-022-01589-5. Epub 2022 Apr 28.
The accumulation of amyloid-β protein (Aβ) plays an early role in the pathogenesis of Alzheimer's disease (AD). The precise mechanism of how Aβ accumulation leads to synaptic dysfunction and cognitive impairment remains unclear but is likely due to small soluble oligomers of Aβ (oAβ). Most studies have used chemical synthetic or cell-secreted Aβ oligomers to study their pathogenic mechanisms, but the Aβ derived from human AD brain tissue is less well characterized. Here we review updated knowledge on the extraction and characterization of bioactive human AD brain oAβ and the mechanisms by which they cause hippocampal synaptic dysfunction. Human AD brain-derived oAβ can impair hippocampal long-term potentiation (LTP) and enhance long-term depression (LTD). Many studies suggest that oAβ may directly disrupt neuronal NMDA receptors, AMPA receptors and metabotropic glutamate receptors (mGluRs). oAβ also impairs astrocytic synaptic functions, including glutamate uptake, D-serine release, and NMDA receptor function. We also discuss oAβ-induced neuronal hyperexcitation. These results may suggest a multi-target approach for the treatment of AD, including both oAβ neutralization and reversal of glutamate-mediated excitotoxicity.
淀粉样β蛋白（Aβ）的积累在阿尔茨海默病（AD）的发病机制中起早期作用。Aβ积累如何导致突触功能障碍和认知障碍的确切机制尚不清楚，但可能是由于Aβ的小可溶性寡聚体（oAβ）。大多数研究使用化学合成或细胞分泌的Aβ寡聚体来研究其致病机制，但源自人类AD脑组织的Aβ特征尚不明确。在此，我们综述了关于生物活性人类AD脑oAβ的提取和表征及其导致海马突触功能障碍机制的最新知识。源自人类AD脑的oAβ可损害海马长时程增强（LTP）并增强长时程抑制（LTD）。许多研究表明，oAβ可能直接破坏神经元N-甲基-D-天冬氨酸受体（NMDA受体）、α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPA受体）和代谢型谷氨酸受体（mGluRs）。oAβ还损害星形胶质细胞的突触功能，包括谷氨酸摄取、D-丝氨酸释放和NMDA受体功能。我们还讨论了oAβ诱导的神经元过度兴奋。这些结果可能提示一种治疗AD的多靶点方法，包括oAβ中和以及逆转谷氨酸介导的兴奋性毒性。
