Multimerization of TREM2 is impaired by Alzheimer's disease–associated variants

Abstract

AbstractINTRODUCTIONThe immune receptor triggering receptor expressed on myeloid cells 2 (TREM2) is among the strongest genetic risk factors for Alzheimer's disease (AD) and is a therapeutic target. TREM2 multimers have been identified in crystallography and implicated in the efficacy of antibody therapeutics; however, the molecular basis for TREM2 multimerization remains poorly understood.METHODSWe used molecular dynamics simulations and binding energy analysis to determine the effects of AD‐associated variants on TREM2 multimerization and validated with experimental results.RESULTSTREM2 trimers remained stably bound, driven primarily by salt bridge between residues D87 and R76 at the interface of TREM2 units. This salt bridge was disrupted by the AD‐associated variants R47H and R98W and nearly ablated by the D87N variant. This decreased binding among TREM2 multimers was validated with co‐immunoprecipitation assays.DISCUSSIONThis study uncovers a molecular basis for TREM2 forming stable trimers and unveils a novel mechanism by which TREM2 variants may increase AD risk by disrupting TREM2 oligomerization to impair TREM2 normal function.Highlights Triggering receptor expressed on myeloid cells 2 (TREM2) multimerization could regulate TREM2 activation and function. D87–R76 salt bridges at the interface of TREM2 units drive the formation of stable TREM2 dimers and trimers. Alzheimer's disease (AD)–associated R47H and R98W variants disrupt the D87–R76 salt bridge. The AD‐associated D87N variant leads to complete loss of the D87–R76 salt bridge.