Drugs repositioning to target TREM2 in Alzheimer disease

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Single amino acid variants in 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 ligands in the body, further affecting TREM2-mediated immune activation in AD. Identifying the available drugs as TREM2 ligands and understanding how the drugs regulate TREM2-mediated immune activation, could reposition the available drugs to target TREM2 and aid the development of combined drug therapy for AD treatment. The central hypothesis of the proposed study is that the available drugs, including FDA-approved drugs, could bind TREM2 at either basic and/or hydrophobic binding site, allosteric effect of drugs at TREM2 either or two binding sites could regulate ligand binding at both sites to modulate TREM2-mediated immune activation in AD, and compensate for the loss of TREM2-mediated immune activities by AD-associated TREM2 variants. We will test the hypothesis with three Aims with integrated computational and experimental approaches. Aim 1 is to identify available drugs bound basic or/and hydrophobic binding sites on TREM2 with unbiased virtual screening and biophysical and biological experimental validation. Aim 2 is to characterize the interactions of the available drugs with TREM2 and determine the allosteric effect of available drugs binding at basic and hydrophobic TREM2 binding sites, and on TREM2-mediated immune activation. Aim 3 is to determine whether the available drugs bound TREM2 could counteract the loss of TREM2-ApoE binding and its mediated immune activities caused by AD- associated TREM2 variants. New knowledge gained from this study could have high impact for AD research and treatment by repositioning the available drugs to target TREM2 and further the insight into available drugs modulating TREM2-mediated immune activation, offering a molecular basis for strategy development of using available drugs including drug combinations to target TREM2 for AD treatment. Investigating novel TREM2 functional mechanism in AD at a fundamental level  how TREM2 activation by available drugs at basic and/or hydrophobic sites and whether and how available drugs compensate for the loss of TREM2 immune activity by AD-associated variants  is the necessary first step. Innovations of study include: 1) This will be the first study to identify available drugs as TREM2 ligand by targeting both TREM2 basic and hydrophobic sites in a more conclusive manner with unbiased virtual screening and validation with biophysical binding and biological cellular function experiments. 2) Results from this study will unveil novel findings about the allosteric effects of available drugs binding at either TREM2 binding site, on TREM2 binding AD pathology related ligand in the body including ApoE, and on TREM2-mediated immune activation. 3) Research outcomes could propose targeting TREM2 with available drugs currently used for other conditions to compensate for loss of TREM2-mediated immune activities by AD-associated variants for AD treatment.