# Using human iPSC derived microglia and chimeric models to examine the role of PLCG2 in Alzheimers disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2022 · $546,576

## Abstract

ABSTRACT
Alzheimer disease (AD) is the leading cause of age-related dementia, affecting over 5 million people in the
United States alone. Unfortunately, current therapies are largely palliative and several promising drug
candidates have failed in late-stage clinical trials. Hence, there is an urgent need to improve our understanding
of the mechanisms that drive the development and progression of AD. As the primary innate immune cell of the
brain, microglia have been implicated in the pathogenesis of AD for several decades. But precisely how
microglia contribute to AD and the degree to which this changes with disease duration remains unclear. Recent
genetic studies have uncovered several AD risk genes that are highly expressed in microglia. By studying
these genes in induced pluripotent stem cell (iPSC)-derived human microglia, we and others aim to advance
our understanding of both the normal and disease-associated functions of these AD risk genes. One recently
discovered mutation occurs in the microglia-enriched gene PLCG2 (Phospholipase C Gamma 2) and codes for
a protective allele associated with a reduced chance of developing AD. This mutation is particularly interesting
as PLCG2 encodes a transmembrane signaling enzyme that plays a critical role in calcium signaling. Calcium
signaling is in turn central to nearly every facet of microglial function including phagocytosis, directed migration,
inflammasome activation, and induction of two master regulators of immune gene transcription; NFAT and
NfkB. We therefore propose to use CRISPR gene editing to produce isogenic iPSCs that express the AD
protective mutation in PLCG2. We will then differentiate these cells into microglia and examine the impact of
PLCG2 manipulations on microglial gene expression, calcium signaling and function. By combining CRISPR
gene editing, microglial differentiation, and a novel chimeric model of AD we aim to overcome several critical
barriers to microglial research and determine the impact of PLCG2 mutations on human microglial gene
expression and function both in vitro and in vivo.
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## Key facts

- **NIH application ID:** 10415087
- **Project number:** 5R01AG061895-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Hayk Davtyan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $546,576
- **Award type:** 5
- **Project period:** 2018-09-30 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10415087

## Citation

> US National Institutes of Health, RePORTER application 10415087, Using human iPSC derived microglia and chimeric models to examine the role of PLCG2 in Alzheimers disease (5R01AG061895-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10415087. Licensed CC0.

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