Matsuzaki Katsumi, Kato Koichi, Yanagisawa Katsuhiko
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Biochim Biophys Acta. 2010 Aug;1801(8):868-77. doi: 10.1016/j.bbalip.2010.01.008. Epub 2010 Feb 1.
Clarification of the molecular and cellular mechanisms underlying the assembly of amyloid beta-protein (Abeta) into insoluble fibrils in the brain has been one of the biggest challenges in the research on Alzheimer disease (AD). We previously identified a novel Abeta species, which was characterized by its tight binding to GM1 ganglioside (GM1), in the brain showing early pathological changes of AD. The ganglioside-bound Abeta (GAbeta) possessed unique characteristics, including its altered immunoreactivity, which suggests its distinct conformation from native Abeta, and its strong potency to accelerate Abeta assembly into fibrils. On the basis of these characteristics, it was hypothesized that Abeta adopts an altered conformation following interaction with GM1, leading to the generation of GAbeta, and then GAbeta acts as an endogenous seed for Alzheimer amyloid in the brain. To date, various in vitro and in vivo studies on GAbeta have revealed how Abeta binds to gangliosides, i.e., what are the favorable physicochemical and neurobiological conditions for generating GAbeta, and what is the pathological significance of ganglioside-induced Abeta assembly in the development of AD. Interestingly, GAbeta is favorably generated in the unique ganglioside-enriched (clustered), raft-like microdomains; moreover, amyloid fibrils formed in the presence of gangliosides are neurotoxic. Furthermore, the conformational change of Abeta in the presence of ganglioside has been characterized by an NMR study. In this review, we focus on the recent progress of GAbeta studies and highlight the possibility that ganglioside binding is the initial and common step in the development of a part of human misfolding-type amyloidoses, including AD.
阐明β-淀粉样蛋白（Aβ）在大脑中组装成不溶性纤维的分子和细胞机制一直是阿尔茨海默病（AD）研究中最大的挑战之一。我们之前在显示AD早期病理变化的大脑中鉴定出一种新型Aβ物种，其特征是与GM1神经节苷脂（GM1）紧密结合。与神经节苷脂结合的Aβ（G-Aβ）具有独特的特性，包括其改变的免疫反应性，这表明其与天然Aβ具有不同的构象，以及其加速Aβ组装成纤维的强大能力。基于这些特性，有人提出假设，Aβ与GM1相互作用后会采用改变的构象，导致G-Aβ的产生，然后G-Aβ作为大脑中阿尔茨海默淀粉样蛋白的内源性种子。迄今为止，对G-Aβ的各种体外和体内研究已经揭示了Aβ如何与神经节苷脂结合，即产生G-Aβ的有利物理化学和神经生物学条件是什么，以及神经节苷脂诱导的Aβ组装在AD发展中的病理意义是什么。有趣的是，G-Aβ在独特的富含神经节苷脂（聚集）的筏样微结构域中很容易产生；此外，在神经节苷脂存在下形成的淀粉样纤维具有神经毒性。此外，通过核磁共振研究对神经节苷脂存在下Aβ的构象变化进行了表征。在这篇综述中，我们关注G-Aβ研究的最新进展，并强调神经节苷脂结合可能是包括AD在内的部分人类错误折叠型淀粉样变性疾病发展的初始和共同步骤。
