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

Area of Science:

• Neuroscience
• Pathology
• Biochemistry

Background:

• Alzheimer's disease (AD) pathogenesis involves pathogenic protein aggregates.
• Genetic links in sporadic AD implicate apolipoprotein E (APOE) and microglial functions.
• The initiation of AD's pathological cascade remains incompletely understood.

Purpose of the Study:

• To investigate the role of apolipoprotein E (APOE) aggregation in Alzheimer's disease (AD) initiation.
• To identify fibrillary APOE aggregates in AD models and human brains.
• To elucidate the mechanism by which APOE aggregation triggers amyloid-beta (Aβ) amyloidosis.

Main Methods:

• Generation of a transgenic knockin mouse model expressing HaloTag-tagged APOE.
• Optimization of biochemical protocols for APOE purification.
• Identification and characterization of fibrillary APOE aggregates using biochemical and staining techniques.

Main Results:

• Fibrillary APOE aggregates were identified in mice with amyloid-beta (Aβ) amyloidosis and in human AD brain autopsies.
• APOE aggregates stained positive for β sheet-binding dyes.
• These APOE aggregates initiated Aβ amyloidosis within the endo-lysosomal system of microglia, influenced by lipid metabolism and JAK/STAT signaling.

Conclusions:

• Microglial endocytic uptake and aggregation of APOE can initiate Aβ plaque formation in Alzheimer's disease.
• This study proposes a novel model for the onset of Aβ amyloidosis in AD.
• Microglial lipid metabolism and JAK/STAT signaling play a role in APOE-mediated Aβ amyloidosis.