Microglial APOE3 Christchurch protects neurons from Tau pathology in a human iPSC-based model of Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder characterized by extracellular amyloid plaques and neuronal Tau tangles. A recent study found that the APOE3 Christchurch (APOECh) variant could delay AD progression. However, the underlying mechanisms remain unclear. In this study, we established neuron-microglia co-cultures and neuroimmune organoids using isogenic APOE3 and APOECh microglia derived from human induced pluripotent stem cells (hiPSCs) with PSEN1 mutant neurons or brain organoids. We show that APOECh microglia are resistant to Aβ-induced lipid peroxidation and ferroptosis and therefore preserve the phagocytic activity and promote pTau clearance, providing mechanistic insights into the neuroprotective role of APOE3Ch microglia. Moreover, we show that an APOE mimetic peptide can mimic the protective effects of APOECh microglia. These findings demonstrate that the APOECh microglia plays a causal role in microglial neuroprotection, which can be exploited for therapeutic development for AD.
Competing Interests: Declaration of interests F.L. and J.F.A.-V. are co-inventors on a patent application concerning the use of APOE Christchurch-related therapeutics. J.F.A.-V. is also a co-founder of Epoch Biotech, a company focused on developing therapies inspired by protected cases.
(Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)