Paper

Microglia Detect Externalized Phosphatidylserine on Synapses for Elimination via TREM2 in Alzheimer's Disease Models

Chang, Sunghoe, Childs, Thomas, Toomey, Christina E, Sokolova, Dimitra, Lachica, Joanne I, De Schepper, Sebastiaan, Jurcakova, Natalia, Hardy, John, Lashley, Tammaryn, Rueda-Carrasco, Javier, Ge, Judy Z, Hong, Soyon, Stevens, Beth, Sang-Eun, Lee, Freeman, Oliver J

2022

Overview

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. Competing Interest Statement OJF is employed by AstraZeneca. The following patents have been granted or applied for: PCT/2015/010288, US14/988387 and EP14822330 (SH).

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Alzheimer's disease / Animal models / Apoptosis / Macrophages / Microglia / Myeloid cells / Neurodegenerative diseases / Neuroscience / Phagocytosis / Phosphatidylserine / β-Amyloid