PROJECT SUMMARY/ABSTRACT Recent genome-wide association studies and studies using mouse models of Alzheimer’s disease (AD) have identified a microglial receptor TREM2 (triggering receptor expressed on myeloid cells 2) as a new therapeutic target of AD. To develop effective therapeutic strategies, a comprehensive mechanistic understanding of TREM2 functions is needed. However, it has been challenging due to the complexity associated with TREM2 and a lack of research tools. Although many genetic tools are available, few chemical biology tools have been developed to study TREM2 biology. The long-term research goal is to understand the detailed mechanism of TREM2 functions during AD pathogenesis and identify novel therapeutic targets and strategies. The main objective of this proposal is to develop chemical biology tools to study TREM2 glycosylation, identify the receptor of sTREM2, and investigate the activation mechanism of TREM2. This objective will be accomplished with three aims. Aim 1 is to develop a robust synthetic method to produce TREM2 ectodomain with homogenous glycans and examine the effect of glycosylation on TREM2 folding, stability, and binding to its ligands. Aim 2 is to develop sTREM2 probes with photo-reactive groups for protein cross-linking and enrichment tags for affinity purification. These probes will be applied to identify the sTREM2 receptor. Aim 3 is to develop constrained peptides to bind and activate TREM2 signaling, allowing a mechanistic understanding of TREM2 activation. The proposal is innovative because 1) innovative hypothesis that altered glycosylation patterns by terminal sialylation can affect TREM2 functions, challenging the existing view of TREM2 glycosylation and 2) it will yield several novel chemical biology tools available to the scientific community to study TREM2. The proposal is significant because 1) it will increase our understanding of the complex TREM2 biology, 2) it will identify a sTREM2 receptor, a potential new therapeutic target of AD, and 3) it will yield constrained peptide agonists of TREM2 that can be further optimized as drug candidates for preclinical testing.

PROJECT NARRATIVE Alzheimer’s disease (AD) affects more than 5 million people in the US. Recent studies have identified TREM2 as a new therapeutic target against AD. This proposal aims to develop tools to gain a further mechanistic understanding of TREM2 function, which could enable the development of more effective therapeutics targeting TREM2.