# Investigating the role of MS4As during Alzheimer's disease

> **NIH NIH F31** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $34,114

## Abstract

Project Summary/Abstract
Alzheimer’s Disease (AD) is the most common neurodegenerative disease in the world and the 6th leading
cause of death in the United States. Despite significant effort, current AD therapies are highly limited in both
number and efficacy. Hope for new therapeutic interventions has emerged from recent genome-wide
association studies (GWAS), which have identified genes whose mutations are linked to altered AD
susceptibility. One of the strongest and most reproducible genetic associations with altered AD risk are
members of the Membrane Spanning 4a (MS4A) gene family. In fact, current genetic data suggest that MS4A
polymorphisms account for approximately 10% of all AD cases. However, a limited understanding of MS4As
has hindered the development of therapies targeting these proteins. Single cell transcriptional profiling has
revealed that the Ms4a genes genetically linked to AD are selectively expressed in a subset of microglia, the
resident innate immune cells of the central nervous system. Furthermore, MS4A-positive subsets of microglia
display a phenotype similar to microglia seen in neurodegenerative disease states, necessitating inquiry into
the role of MS4As in microglia. We found that Ms4a-positive microglia are enriched for phagocytic machinery
versus Ms4a-negative microglia, and animals deficient for individual Ms4a family members have significantly
reduced expression of genes important for phagocytosis compared to wild-type (WT) animals. Microglial
phagocytosis is a dynamic process by which brain debris, dying cells, unwanted synaptic connections, and
toxic molecules are eliminated and disruption of this process is thought to underlie numerous neurological
disorders, including AD. Thus, this proposal will test the hypothesis that MS4As regulate microglial
phagocytosis and alter AD pathogenesis. To test this hypothesis, aim 1 will examine microglia phagocytosis of
synapses, dead neurons, and amyloid-beta 42- one of the neurotoxic, pathogenic agents of AD- both in vitro
and in vivo using Ms4a-deficient and WT microglia. These experiments will characterize the role of MS4As in
microglia, and provide insight into how MS4As affect microglial phagocytosis. Aim 2 will investigate the role of
MS4As in AD pathogenesis. Although GWAS studies have strongly linked MS4A polymorphisms to AD
susceptibility, the role of MS4A genes in AD is unknown. Some MS4A alleles confer AD protection while others
increase AD susceptibility, and MA4A polymorphisms are often located in non-coding regions of these genes.
To investigate whether MS4As are protective against or contributive toward AD, mice that are homozygous
deficient for individual Ms4a family members will be crossed to the 5XFAD mouse model of AD and
pathological features of AD, including behavioral defects in memory, amyloid beta plaque formation,
microgliosis, neuronal loss, and synapse elimination will be assessed. Together, these aims will provide
fundamental new insight into the...

## Key facts

- **NIH application ID:** 10450772
- **Project number:** 5F31AG069495-03
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Thuyvan Hua Luu
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $34,114
- **Award type:** 5
- **Project period:** 2020-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450772

## Citation

> US National Institutes of Health, RePORTER application 10450772, Investigating the role of MS4As during Alzheimer's disease (5F31AG069495-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10450772. Licensed CC0.

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