# TREM2-endogenous ligand interactions in Alzheimer disease

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2022 · $425,582

## Abstract

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.

## Key facts

- **NIH application ID:** 10487465
- **Project number:** 5R01AG068395-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Yuhua Song
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $425,582
- **Award type:** 5
- **Project period:** 2021-09-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10487465

## Citation

> US National Institutes of Health, RePORTER application 10487465, TREM2-endogenous ligand interactions in Alzheimer disease (5R01AG068395-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10487465. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*