Apolipoprotein E aggregation in microglia initiates Alzheimer’s disease pathology by seeding β-amyloidosis

The seeded growth of pathogenic protein aggregates underlies the pathogenesis of Alzheimer’s disease (AD), but how this pathological cascade is initiated is not fully understood. Sporadic AD is linked genetically to apolipoprotein E (APOE) and other genes expressed in microglia related to immune, lipid, and endocytic functions. We generated a transgenic knockin mouse expressing HaloTag-tagged APOE and optimized experimental protocols for the biochemical purification of APOE, which enabled us to identify fibrillary aggregates of APOE in mice with amyloid-β (Aβ) amyloidosis and in human AD brain autopsies. These APOE aggregates that stained positive for β sheet-binding dyes triggered Aβ amyloidosis within the endo-lysosomal system of microglia, in a process influenced by microglial lipid metabolism and the JAK/STAT signaling pathway. Taking these observations together, we propose a model for the onset of Aβ amyloidosis in AD, suggesting that the endocytic uptake and aggregation of APOE by microglia can initiate Aβ plaque formation. [Display omitted] •Apolipoprotein E aggregates can serve as seeds for Aβ plaque pathology•APOE aggregation occurs within the endo-lysosomal system of microglia•APOE internalization is regulated by cholesterol metabolism in microglia•Interferon-activated microglia facilitate the aggregation process Pathogenic protein aggregation drives Alzheimer’s disease, but how it is initiated remains unclear. By generating a APOE-HaloTag knockin mouse model and optimizing APOE purification techniques, Kaji et al. identify fibrillary APOE aggregates that can serve as seeds for Aβ plaque formation. This aggregation occurs within the endo-lysosomal system of microglia and is regulated by cholesterol metabolism.