TREM2-endogenous ligand interactions in Alzheimer disease

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PROJECT SUMMARY Single amino acid variants in triggering receptor expressed on myeloid cells 2 (TREM2) have been identified by genome-wide association studies to be one of the strongest genetic risk factors for late-onset Alzheimer’s disease (AD). AD-associated variants in TREM2 impair TREM2’s ability to bind and signal in response to endogenous ligands. The molecular mechanisms of TREM2 in AD remain not fully understood, in part due to the lack of conclusive identities for TREM2’s endogenous ligands and the lack of a good understanding of how different endogenous ligands interact with TREM2 to affect TREM2 functions. The central hypothesis is that AD-associated variants at TREM2 basic site allosterically regulate endogenous ligands bound at the hydrophobic site of TREM2, and allosteric co-stimulation by endogenous ligands at both basic and hydrophobic binding sites could enhance TREM2 immune activity in AD. The objective is to identify endogenous ligands that bind at the basic and/or hydrophobic sites of TREM2, determine the allosteric effects of ligand binding at either binding site, and determine the effect of AD-associated TREM2 variants on endogenous ligands binding to TREM2. We will test the hypothesis and implement the objective with three Aims. Aim 1 is to identify endogenous ligands of the basic and hydrophobic binding sites on TREM2. Aim 2 is to determine the allosteric effects of endogenous ligand binding at both TREM2 binding sites. Aim 3 is to determine the effect of AD-associated TREM2 variants on endogenous ligands binding to TREM2. New knowledge could have high impact for AD research and treatment by opening an unrecognized avenue of targeting both TREM2 basic and hydrophobic sites to identify TREM2 endogenous ligands and to promote TREM2-regulated immune activation. Research outcomes could aid the development of novel therapeutic strategies, such as combined drug therapy, to enhance TREM2-mediated cellular activities and to compensate the loss of TREM2 function by AD-associated variants for AD treatment. Although immediate potential application for this study is AD pathogenesis, impact on other neurodegenerative and inflammatory diseases affected by TREM2 activation may be enormous. Innovations include 1) this will be the first study to identify TREM2 endogenous ligands by targeting both TREM2 basic and hydrophobic binding sites in a more conclusive manner using the combined in silico virtual screening, biophysical and biological experiments; 2) Results will unveil novel findings that AD- associated variants at TREM2 basic site allosterically regulate endogenous ligand bound at TREM2 hydrophobic site, and allosteric co-stimulation by endogenous ligands at both basic and hydrophobic sites could enhance TREM2-regulated immune activity in AD, providing novel insight into etiology of AD.