Apolipoprotein E aggregation in microglia, seeds β-amyloidosis in Alzheimer's disease

The seeded proliferation of harmful protein aggregates is fundamental to the pathophysiology of Alzheimer's disease (AD), although the initiation of this pathological cascade remains incompletely elucidated. Kaji et al. have developed a transgenic knockin mouse that expresses HaloTag-tagged APOE and discovered fibrillary aggregates of APOE in animals exhibiting amyloid-β (Aβ) amyloidosis. The APOE aggregates that tested positive for β-sheet-binding dyes induced Aβ amyloidosis in the endo-lysosomal system of microglia, a process modulated by microglial lipid metabolism and the JAK/STAT signaling pathway, indicating that the endocytic uptake and aggregation of APOE by microglia can initiate Aβ-plaque formation.