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

Area of Science:

• Neuroscience
• Genetics
• Pathology

Background:

• A rare APOE3 Christchurch (APOE3ch) mutation was linked to resistance to autosomal dominant Alzheimer's Disease (AD).
• The protective mechanism of APOE3ch against AD, particularly its role in amyloid-beta (Aβ) and tau pathology, remains unclear.

Purpose of the Study:

• To investigate the functional impact of the APOE3ch mutation on Alzheimer's disease pathology in a humanized mouse model.
• To determine if APOE3ch influences amyloid and tau seeding and spreading, and the associated microglial response.

Main Methods:

• Generated a humanized APOE3ch knock-in mouse model.
• Crossed the APOE3ch mice with an Aβ plaque-depositing model.
• Injected AD-tau brain extract to assess tau seeding and spreading in the presence or absence of amyloid.
• Analyzed microglial and myeloid cell responses, and APOE3ch binding to heparin sulfate proteoglycans.

Main Results:

• APOE3ch expression led to peripheral dyslipidemia and reduced plaque-associated tau pathology.
• Observed decreased amyloid response and enhanced microglial activation around Aβ plaques.
• Demonstrated increased myeloid cell phagocytosis and degradation of tau aggregates, linked to weaker APOE3ch binding to heparin sulfate proteoglycans.
• APOE3ch suppressed Aβ-induced tau seeding and spreading by influencing microglial response to Aβ plaques.

Conclusions:

• APOE3ch confers protection against Aβ-induced tauopathy through modulation of microglial responses and enhanced tau aggregate clearance.
• These findings suggest novel therapeutic strategies targeting APOE3ch-mediated pathways for Alzheimer's disease and related tauopathies.