# Impact of PLCG2 Alzheimer's Disease Risk Variants on Microglia Biology and Disease Pathogenesis

> **NIH NIH RF1** · INDIANA UNIVERSITY INDIANAPOLIS · 2021 · $2,333,674

## Abstract

PROJECT SUMMARY
 Alzheimer’s disease (AD) and other neurodegenerative diseases are typified by a robust
microglial-mediated immune response. Genetic studies have demonstrated that many of the
genes that confer altered risk for AD are those involved in the innate immune response and are
expressed primarily in microglia, including phospholipase C gamma 2 (PLCG2). PLCG2 is a
critical signaling element for a variety of immune receptors and is a key regulatory hub gene for
immune signaling. The primary objective of this proposal is to determine the role of PLCG2 in AD
pathogenesis. GWAS studies have demonstrated that the PLCG2 P522R variant is associated
with reduced AD risk. Our laboratory has identified a novel SNP (rs617749044) associated with
elevated AD risk encoding the PLCG2 M28L variant. The overall objectives in this application are
to elucidate the effect of these PLCG2 variants on AD pathogenesis using rodent models of AD
and dissect the molecular mechanisms by which PLCG2 variants alter microglia function. The
hypotheses are that the M28L variant is a loss of function allele, and conversely the P522R is
protective with respect to AD pathogenesis in our murine models. The experiments proposed in
this application are entirely novel and allow, for the first time, a unique, comprehensive analysis
of an AD risk gene whose genetic variants confer both protection and risk for AD. Preliminary data
generated by the applicant suggests that in a rodent model of AD, the M28L variant had
accelerated and exacerbated disease related pathology and conversely the P522R variant
appeared to attenuate disease severity and progression. The hypotheses will be tested by
pursuing three specific aims: 1) Determine AD-related phenotypes altered by loss and gain of
function PLCG2 variants in an amyloidogenic model of AD; 2) Identify molecular signatures and
pathways in microglia that are associated with protective or risk PLCG2 variants in an
amyloidogenic model of AD; and 3) Evaluate the mechanisms through which PLCG2 variants
affect intracellular signaling in microglia. These studies are essential prerequisites for the
development of PLCG2-directed therapeutics.

## Key facts

- **NIH application ID:** 10317333
- **Project number:** 1RF1AG074566-01
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** STEPHANIE J BISSEL
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $2,333,674
- **Award type:** 1
- **Project period:** 2021-09-30 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10317333

## Citation

> US National Institutes of Health, RePORTER application 10317333, Impact of PLCG2 Alzheimer's Disease Risk Variants on Microglia Biology and Disease Pathogenesis (1RF1AG074566-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10317333. Licensed CC0.

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