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

IF 7.5 1区生物学 Q1 CELL BIOLOGY Cell reports Pub Date : 2024-11-28 DOI:10.1016/j.celrep.2024.114982

Guoqiang George Sun, Cheng Wang, Randall C Mazzarino, Paula Andrea Perez-Corredor, Hayk Davtyan, Mathew Blurton-Jones, Francisco Lopera, Joseph F Arboleda-Velasquez, Yanhong Shi

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Abstract

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.

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.