# High Throughput Screen to Discover Modulators of TREM2 Activity

> **NIH NIH R01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2020 · $415,290

## Abstract

PROJECT SUMMARY
Currently over 5 million people are living with Alzheimer’s disease (AD) in the US. Unfortunately, no disease
modifying therapies are yet approved, resulting in an enormous unmet medical need and burden on society.
Genetic studies on patients with Late Onset AD (LOAD), which accounts for the vast majority of AD, point to
defects in microglial function as the cause. Recently, we and others have identified mutations in the gene
encoding TREM2 (triggering receptor expressed on myeloid cells 2) that correlate with a significantly increased
risk of developing LOAD. In particular, the TREM2 R47H variant is associated with a risk similar to that of
APOE4, previously the only well-established risk factor for LOAD. In the central nervous system, TREM2 is
selectively expressed on microglia and is recognized to regulate the production of inflammatory cytokines,
phagocytosis of apoptotic neurons and cell survival. TREM2 is a type 1 membrane protein of the Ig superfamily
with a short cytoplasmic tail that interacts with–and signals through–DNAX-activating protein of 12 kDa
(DAP12). In an exciting development, we and others have shown that TREM2 binds APOE and Clusterin
(another apolipoprotein linked genetically to AD) and that mutations in TREM2 (e.g. R47H) reduce the binding
of these ligands and also of oligomeric Aβ. Our current hypothesis is that impaired signaling through TREM2-
DAP12 results in an altered immune response by microglia and this contributes to AD pathogenesis. In this
revised application, we propose a high throughput screen of a large chemical library to identify compounds that
bind to and modulate the function of TREM2 as a first step in translating these new biological insights into
therapeutics. An innovative protein thermal shift (PTS) assay has been established that uses purified TREM2
to identify compounds that bind. This assay has been fully optimized in a 384 well format and as a
demonstration of assay readiness, 45,000 compounds have been screened (Z’-parameter >0.7). Multiple hits
from pilot screens were identified that dose dependently stabilized TREM2-but not control protein. A battery of
downstream assays has been developed to establish a critical path-testing funnel. Specifically, orthogonal
biophysical assays to confirm that hits physically bind TREM2 and secondary cellular assays to evaluate if hits
affect the shedding of TREM2, alter the phosphorylation state of DAP12, and/or affect the activation state and
properties of microglia. This proposal builds on data from the applicants, an established team from Sanford
Burnham Prebys (Drs. Jackson, Sergienko and Xu) and Tanz CNRD, University of Toronto (Dr. St. George-
Hyslop) who have been working together for the past 2 years, supported by philanthropic funds. The overall
goal of this proposal is to generate a “toolbox” of chemical probes (agonists, antagonists, allosteric modulators)
that can be used to explore the biology of TREM2 and its role in LOAD. As the ...

## Key facts

- **NIH application ID:** 9879696
- **Project number:** 5R01AG058446-03
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** Michael Jackson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $415,290
- **Award type:** 5
- **Project period:** 2018-03-15 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9879696

## Citation

> US National Institutes of Health, RePORTER application 9879696, High Throughput Screen to Discover Modulators of TREM2 Activity (5R01AG058446-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9879696. Licensed CC0.

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