PDF(Pubmed)
Abstract：
Which isoforms of apolipoprotein E (apoE) we inherit determine our risk of developing late-onset Alzheimer\'s Disease (AD), but the mechanism underlying this link is poorly understood. In particular, the relevance of direct interactions between apoE and amyloid-β (Aβ) remains controversial. Here, single-molecule imaging shows that all isoforms of apoE associate with Aβ in the early stages of aggregation and then fall away as fibrillation happens. ApoE-Aβ co-aggregates account for ~50% of the mass of diffusible Aβ aggregates detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. We show how dynamic interactions between apoE and Aβ tune disease-related functions of Aβ aggregates throughout the course of aggregation. Our results connect inherited APOE genotype with the risk of developing AD by demonstrating how, in an isoform- and lipidation-specific way, apoE modulates the aggregation, clearance and toxicity of Aβ. Selectively removing non-lipidated apoE4-Aβ co-aggregates enhances clearance of toxic Aβ by glial cells, and reduces secretion of inflammatory markers and membrane damage, demonstrating a clear path to AD therapeutics.
摘要：
我们继承的载脂蛋白E（apoE）的同工型决定了我们发展迟发性阿尔茨海默病（AD）的风险，但是这种联系背后的机制知之甚少。特别是,apoE与淀粉样蛋白β（Aβ）之间直接相互作用的相关性仍存在争议。这里,单分子成像显示，apoE的所有同工型在聚集的早期阶段与Aβ相关，然后随着纤颤的发生而消失。ApoE-Aβ共聚集体占在具有较高风险APOE4基因的纯合子的额叶皮层中检测到的可扩散Aβ聚集体的质量的约50％。我们展示了apoE和Aβ之间的动态相互作用如何在整个聚集过程中调节Aβ聚集体的疾病相关功能。我们的结果通过证明如何将遗传性APOE基因型与患AD的风险联系起来，以同构和脂化特定的方式，apoE调制聚集，Aβ的清除率和毒性。选择性去除非脂化的apoE4-Aβ共聚集体可增强胶质细胞对毒性Aβ的清除，并减少炎症标记物的分泌和膜损伤，证明了AD治疗的明确途径。
