Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK.
UK Dementia Research Institute at University of Cambridge, Cambridge, UK.
Nat Commun. 2024 Jun 1;15(1):4695. doi: 10.1038/s41467-024-49028-z.
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.
我们遗传的载脂蛋白 E（apoE）的异构体决定了我们患上迟发性阿尔茨海默病（AD）的风险，但这种联系的机制还不清楚。特别是，apoE 与淀粉样蛋白-β（Aβ）之间的直接相互作用的相关性仍然存在争议。在这里，单分子成像表明，apoE 的所有异构体都在聚集的早期与 Aβ 结合，然后随着纤维形成的发生而消失。apoE-Aβ 共聚集物占在具有较高风险的 APOE4 基因的纯合子的额皮质中检测到的可扩散 Aβ 聚集物的质量的约 50％。我们展示了 apoE 与 Aβ 之间的动态相互作用如何在整个聚集过程中调节与疾病相关的 Aβ 聚集物的功能。我们的结果通过证明 apoE 如何以异构体和脂质特异性的方式调节 Aβ 的聚集、清除和毒性，将遗传的 APOE 基因型与 AD 的发病风险联系起来。选择性去除非脂化的 apoE4-Aβ 共聚集物可增强神经胶质细胞清除毒性 Aβ 的能力，并减少炎症标志物的分泌和膜损伤，为 AD 治疗提供了明确的途径。
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