# TREM2-TYROBP coupling modulation for the reduction of Alzheimer's-mediated neuroinflammation: a novel pharmacologic therapy

> **NIH NIH F31** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2020 · $45,520

## Abstract

ABSTRACT
Alzheimer's disease (AD), the most common form of dementia, is a crippling neurodegenerative disease that is
growing quickly in prevalence. Currently, there are no FDA approved medications that serve to prevent or
reduce the pathology; all drugs are merely cognitive enhancers used to offset the deficits of dementia.
Genome-wide association studies (GWAS) have been conducted to supplant the already acquired knowledge
surrounding AD pathology and have recently identified one of several genes, Triggering Receptor Expressed
on Myeloid Cells 2 (TREM2), as a genetic node in the risk of developing AD. The main function of TREM2
significant to AD is stimulation of macrophage and neutrophil-mediated inflammatory responses, suggesting
the exacerbation or alleviation of TREM2 to AD pathology is heavily based on chronic, injurious
neuroinflammation as well as amyloid-β clearance. Several scientific studies published within the last five
years have produced mixed results as to whether decreasing the activity of TREM2 with antibody antagonism
or gene knockout mitigates or provokes the pathology of AD. Therefore, further validation of these findings is
warranted, particularly pertaining to modulation of TREM2-TYROBP signaling to assess the effect of increasing
phagocytosis of amyloid-β oligomers and fibrils. In order to pursue this topic, both agonistic and antagonistic
small molecules were screened for and characterized for their potential to modulate TREM2-TYROBP
signaling in vitro. Using an in-house developed luciferase assay validated as a robust method for assessing
TREM2-TYROBP signaling in Human Embryonic Kidney cells (HEK293) transfected with a construct of both
genes, we identified several hits as agonists or antagonists of TREM2-TYROBP coupling. Our next aim is to
validate these hits in BV2 murine microglial cells and primary cultured murine microglia. After further
characterization of these compounds in vitro, they will be tested in vivo for toxicology, bioavailability, and
therapeutic efficacy in a knock-in mouse model of AD using APPNL-G-F knock-in mice. Therapeutic efficacy will
be evaluated in consideration of reduced amyloid burden and reduced age-related cognitive decline as
assessed with biochemistry, immunohistochemistry and behavioral examinations, respectively. Successful
completion of these studies will 1) contribute to the understanding of TREM2 and its in role AD pathology and
2) present highly validated compounds as tools for further research in this area.

## Key facts

- **NIH application ID:** 9916682
- **Project number:** 5F31AG057170-03
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Kevin Clayton
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2018-05-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9916682

## Citation

> US National Institutes of Health, RePORTER application 9916682, TREM2-TYROBP coupling modulation for the reduction of Alzheimer's-mediated neuroinflammation: a novel pharmacologic therapy (5F31AG057170-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9916682. Licensed CC0.

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