APOE3ch alters microglial response and suppresses Aβ-induced tau seeding and spread

Highlights•APOE3ch suppresses Aβ pathology and Aβ-induced tau seeding and spreading in vivo•APOE3ch enhances microglial lysosomal activity and phagocytosis of hTau fibrils•The competitive binding of APOE over hTau to HSPG/LRP1 is weakened by APOE3ch•Less hTau-containing material is secreted by APOE3ch than APOE3 myeloid cellsSummaryA recent case report described an individual who was a homozygous carrier of the APOE3 Christchurch (APOE3ch) mutation and resistant to autosomal dominant Alzheimer's Disease (AD) caused by a PSEN1-E280A mutation. Whether APOE3ch contributed to the protective effect remains unclear. We generated a humanized APOE3ch knock-in mouse and crossed it to an amyloid-β (Aβ) plaque-depositing model. We injected AD-tau brain extract to investigate tau seeding and spreading in the presence or absence of amyloid. Similar to the case report, APOE3ch expression resulted in peripheral dyslipidemia and a marked reduction in plaque-associated tau pathology. Additionally, we observed decreased amyloid response and enhanced microglial response around plaques. We also demonstrate increased myeloid cell phagocytosis and degradation of tau aggregates linked to weaker APOE3ch binding to heparin sulfate proteoglycans. APOE3ch influences the microglial response to Aβ plaques, which suppresses Aβ-induced tau seeding and spreading. The results reveal new possibilities to target Aβ-induced tauopathy.Graphical abstract