Mapping protein interactome of TREM2 and its variants to probe the etiology of Alzheimer's Disease

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Project summary Triggering receptor expressed on myeloid cells 2 (TREM2) recently emerged as a major immune signaling hub that is essential to sustain the microglial response to AD pathology, and enable microglial transition to a disease-associated microglia (DAM) status. Rare variants R47H and R62H in TREM2 significantly increase risks for late-onset Alzheimer’s disease (AD), indicating altered TREM2 signaling is sufficient to drive AD pathology. Despite the exciting genetic studies linking TREM2 variants to AD etiology, the molecular mechanisms underlying this genotype-phenotype relationship are only partially explained. Protein-protein interactions (PPIs) are central to the proper functioning of cellular signaling and regulatory processes, and disruptions of the normal patterns of PPIs are often observed and implicated in human genetic diseases. As such, mapping proteins that interact with TREM2 on a system-wide level is fundamental for understanding molecular machinery of TREM2 pathway and dissecting specific microglial signaling that is altered in AD-associated TREM2 variants. In this application, We propose to map TREM2 protein interactome in microglia use TurboID- based proximity labeling approach (Aim 1), and to profile the change of TREM2 interactome caused by AD-associated variations R47H and R62H (Aim 2). Upon completion, our study will identify novel regulators of TREM2 signaling, and bring insights into the causal mechanisms of TREM2 variants in AD. Knowledge generated from this project will also help design novel therapeutic strategies targeting TREM2 for the treatment of AD.