# Evaluating a novel, orally-active TREM2-targeting drug in AD

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $402,373

## Abstract

Project Summary
 Neuroinflammation, characterized by microglial activation and increased pro-inflammatory cytokine
production, is evident early in Alzheimer's disease (AD) and appears to play an important role in disease
progression. Signaling through TREM2 (Triggering receptor expressed on myeloid cells 2) mediates this
inflammatory response through effects on microglial activation. TREM2 has also been recognized as a risk
factor for AD with missense mutations in the gene being associated with increased risk of AD and elevated
levels of TREM2 in the cerebrospinal fluid correlating with decreased disease severity. Excitingly, TREM2 was
recently shown by members of our study team to be a druggable target by the newly designed, orally available
agent, Sob-AM2. While Sob-AM2 has shown to be neuroprotective in other neurodegenerative disease
models where neuroinflammation and cognitive impairment are also evident, it has not yet been developed for
use in AD. The studies proposed here will begin to fill in these existing gaps in the preclinical testing of Sob-
AM2.
 In Aim 1 we will optimize the concentration of oral Sob-AM2 needed to elicit maximum increases in TREM2
expression in the brain without evoking toxicity. Aims 2 and 3 will utilize the identified dose, determine the
optimal timing of treatment initiation and assess efficacy in AD mouse models. Aim 2 will use the 5xFAD model
of beta-amyloid accumulation while Aim 3 will use the PS19 model of tauopathy to investigate the effects of an
early versus late start of oral Sob-AM2 treatment on the downstream effects of TREM2 activation on AD
pathology as well as neurodegeneration, cognition and neuroinflammation. We will also monitor the
downstream targets of thyroid hormone signaling to identify non-TREM2 related effects of Sob-AM2 as well as
to ensure that there is no evidence of aberrant signaling and that peripheral off-target effects are not seen.
 This work will address critical questions surrounding dosage and treatment duration of the first orally active,
small molecule drug to target TREM2. Given the lack of disease modifying AD therapies, Sob-AM2 is a very
promising candidate drug to develop for use in AD and completion of these essential preclinical studies
described in this project will greatly accelerate its eventual clinical translation.

## Key facts

- **NIH application ID:** 10901961
- **Project number:** 5R01AG079949-02
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Nora E Gray
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $402,373
- **Award type:** 5
- **Project period:** 2023-08-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10901961

## Citation

> US National Institutes of Health, RePORTER application 10901961, Evaluating a novel, orally-active TREM2-targeting drug in AD (5R01AG079949-02). Retrieved via AI Analytics 2026-06-25 from https://api.ai-analytics.org/grant/nih/10901961. Licensed CC0.

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