Background: A 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.
Method: 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. Mouse samples were collected and used for multiple measurements including cholesterol test, WB, ELISA, IF, etc. We also designed and performed in vitro assays to evaluate the phagocytosis, degradation, competitive uptake, exocytosis, etc. RESULT: 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 in vitro.
Conclusion: APOE3ch influences the microglial response to Aβ plaques, which suppresses Aβ-induced tau seeding and spreading.
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