Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer's disease
NATURE COMMUNICATIONS(2024)
摘要
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-beta (A beta) remains controversial. Here, single-molecule imaging shows that all isoforms of apoE associate with A beta in the early stages of aggregation and then fall away as fibrillation happens. ApoE-A beta co-aggregates account for similar to 50% of the mass of diffusible A beta aggregates detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. We show how dynamic interactions between apoE and A beta tune disease-related functions of A beta 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 A beta. Selectively removing non-lipidated apoE4-A beta co-aggregates enhances clearance of toxic A beta by glial cells, and reduces secretion of inflammatory markers and membrane damage, demonstrating a clear path to AD therapeutics.
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