# Drugs repositioning to target TREM2 in Alzheimer disease

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2024 · $587,814

## Abstract

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 availa...

## Key facts

- **NIH application ID:** 10867499
- **Project number:** 5R01AG081228-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Yuhua Song
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $587,814
- **Award type:** 5
- **Project period:** 2023-06-15 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10867499

## Citation

> US National Institutes of Health, RePORTER application 10867499, Drugs repositioning to target TREM2 in Alzheimer disease (5R01AG081228-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10867499. Licensed CC0.

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