RT Journal Article SR Electronic T1 Microglia Detect Externalized Phosphatidylserine on Synapses for Elimination via TREM2 in Alzheimer’s Disease Models JF bioRxiv FD Cold Spring Harbor Laboratory SP 2022.04.04.486424 DO 10.1101/2022.04.04.486424 A1 Javier Rueda-Carrasco A1 Dimitra Sokolova A1 Sang-Eun Lee A1 Thomas Childs A1 Natália Jurčáková A1 Sebastiaan De Schepper A1 Judy Z. Ge A1 Joanne I. Lachica A1 Christina E. Toomey A1 Oliver J. Freeman A1 John Hardy A1 Beth Stevens A1 Tammaryn Lashley A1 Sunghoe Chang A1 Soyon Hong YR 2022 UL http://biorxiv.org/content/early/2022/04/05/2022.04.04.486424.abstract AB Genetic studies implicate phagocytosis pathways in microglia to be a major Alzheimer’s disease (AD)-associated process. Microglia phagocytose synapses in AD mouse models, suggesting a role for microglia in region-specific synapse loss, a pathological hallmark of AD. However, whether specific synapses are targeted for elimination, and if so, how, remains to be elucidated. Here, we show that synapses externalize phosphatidylserine (PtdSer) upon challenge by β-amyloid oligomers, which are then selectively engulfed by microglia. Mechanistically, we find that Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is critical for microglia to sense and preferentially engulf AD synapses. In brains of mice and humans, TREM2 dysfunction leads to exacerbation of apoptotic synapses. Our work altogether suggests a fundamental role for microglia as brain-resident macrophages to remove damaged synapses in AD. We provide mechanistic insight into how TREM2 variants associated with increased risk of developing AD may contribute to defective microglia-synapse function.One-Sentence summary Microglia selectively engulf synapses in Alzheimer-like mouse brains via PtdSer-TREM2 signaling.Competing Interest StatementOJF is employed by AstraZeneca. The following patents have been granted or applied for: PCT/2015/010288, US14/988387 and EP14822330 (SH).