Gladstone Institute of Neurological Disease and University of California, San Francisco, San Francisco, California, USA.
Cold Spring Harb Perspect Med. 2012 Jul;2(7):a006338. doi: 10.1101/cshperspect.a006338.
Evidence for an ever-expanding variety of molecular mediators of amyloid β-protein neurotoxicity (membrane lipids, receptor proteins, channel proteins, second messengers and related signaling cascades, cytoskeletal proteins, inflammatory mediators, etc.) has led to the notion that the binding of hydrophobic Aβ assemblies to cellular membranes triggers multiple effects affecting diverse pathways. It appears unlikely that there are only one or two cognate receptors for neurotoxic forms of Aβ and also that there are just one or two assembly forms of the peptide that induce neuronal dysfunction. Rather, various soluble (diffusible) oligomers of Aβ that may be in dynamic equilibrium with insoluble, fibrillar deposits (amyloid plaques) and that can bind to different components of neuronal and non-neuronal plasma membranes appear to induce complex patterns of synaptic dysfunction and network disorganization that underlie the intermittent but gradually progressive cognitive manifestations of the clinical disorder. Modern analyses of this problem utilize electrophysiology coupled with synaptic biochemistry and behavioral phenotyping of animal models to elucidate the affected circuits and assess the effects of potential therapeutic interventions.
证据表明，淀粉样β蛋白神经毒性的分子介质（膜脂质、受体蛋白、通道蛋白、第二信使和相关信号级联、细胞骨架蛋白、炎症介质等）种类繁多，这使得人们认为疏水性 Aβ 组装体与细胞膜的结合会引发多种影响不同途径的效应。似乎不太可能只有一两个神经毒性形式的 Aβ 的同源受体，也不太可能只有一两个诱导神经元功能障碍的肽的组装形式。相反，各种可溶性（可扩散）的 Aβ 寡聚物可能与不溶性纤维状沉积物（淀粉样斑块）处于动态平衡中，并且可以与神经元和非神经元质膜的不同成分结合，似乎会诱导复杂的突触功能障碍和网络紊乱模式，这是临床疾病间歇性但逐渐进展的认知表现的基础。这个问题的现代分析利用电生理学结合突触生物化学和动物模型的行为表型来阐明受影响的回路，并评估潜在治疗干预的效果。
