# Generation and analysis of new mouse models to determine novel therapeutic targets for Down syndrome-associated cognitive deficits

> **NIH NIH R01** · ROSWELL PARK CANCER INSTITUTE CORP · 2024 · $442,248

## Abstract

PROJECT SUMMARY
Alzheimer’s disease (AD)-associated pathological alterations are universally present in individuals with Down
syndrome (DS) by 40 years of age, and the majority of people (88%) with DS are negatively affected by AD at
65 years of age. Because of this high disease burden, effective treatments for AD would be particularly beneficial
to the DS population, but the complex molecular events that underlie the pathogenesis of AD in DS (AD-DS)—
the key to developing targeted therapies—remain poorly understood. In the proposed research, we will use
CRISPR technology to engineer mutant mice to probe the regulatory roles of MS4A proteins on TREM2 and
microglial activation, which are known to play important roles in the development of AD in both DS and the
general population. TREM2 is a transmembrane protein that is expressed in microglia, and TREM2 functions as
a pattern recognition receptor that detects and binds to Aβ oligomers and induces an innate immune response.
Soluble TREM2 (sTREM2) inhibits Aβ oligomerization and disaggregates preformed Aβ oligomers and
protofibrils, thus inhibiting Aβ fibrillization, and consequently, Aβ-induced neurotoxicity is blocked. Experimental
support for this cascade has been obtained in mouse models, and different levels of TREM2 in cerebrospinal
fluid (CSF) are known to be associated with different disease states in patients with AD. MS4A proteins are
considered among the most important regulators of TREM2 and microglial activation, and MS4A mutations are
closely associated with different levels of TREM2 in CSF and activation of microglia l cells. However, the
functional relationships among TREM2, MS4As, and microglial activation were established mainly through
genome-wide association studies. Presently, in vivo data on how TREM2 and microglial activation are regulated
by MS4As and the consequence in AD-DS are lacking. To fill this important knowledge gap, we plan to examine
Ms4a-mediated regulation of TREM2 in AD-DS in vivo in two engineered mouse models. Afterward, we will
pursue the following phenotyping experiments for each aim: (a) analysis of TREM2 levels in CSF; (b) analysis
of the activation of microglial cells; (c) measurement of the levels of Aβ in mouse brain tissue; (d) examination
of AD-associated neuropathology; and (e) analysis of cognitive deficits. Attainment of these objectives will allow
us to directly test the hypothesis that Ms4a-mediated TREM2 regulation and microglial activation play an
important role in AD-DS for the first time by using our mutant mice. Furthermore, achievement of our goals will
open up a major area for new AD research, with promise for those with or without DS, and bring us closer to
developing effective treatments for AD and other medical conditions associated with TREM2, MS4A, and
microglia.

## Key facts

- **NIH application ID:** 10937797
- **Project number:** 3R01HD109750-03S1
- **Recipient organization:** ROSWELL PARK CANCER INSTITUTE CORP
- **Principal Investigator:** Eugene Yu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $442,248
- **Award type:** 3
- **Project period:** 2022-09-13 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10937797

## Citation

> US National Institutes of Health, RePORTER application 10937797, Generation and analysis of new mouse models to determine novel therapeutic targets for Down syndrome-associated cognitive deficits (3R01HD109750-03S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10937797. Licensed CC0.

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