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 soluble Aβ aggregates detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. 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 inflammation and membrane damage, demonstrating a clear path to AD therapeutics.
Isoforms of Apolipoprotein E (ApoE) 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 in the early stages of aggregation, all isoforms of ApoE associate with Aβ in large co-aggregates, but then fall away as fibrillation happens. Similar large co-aggregates exist in the brains of AD patients, accounting for around 50% of the mass of aggregated Aβ detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. The cellular uptake and toxicity of these large co-aggregates are isoform-dependent, suggesting a mechanistic role for ApoE-Aβ interactions in AD.
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