# Manipulating DNA repair enzymes to examine the interactions between aging and Alzheimers disease with iPSC-derived microglia

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $386,250

## Abstract

Project Summary/Abstract
Microglia are strongly implicated in the pathogenesis of Alzheimer's disease (AD) and recent genetic studies
have identified several microglial-enriched genes that influence AD risk. To study the role of these genes in AD
our lab recently developed a fully-defined approach to differentiate induced pluripotent stem cells (iPSCs) into
microglia. However, reprogramming erases many of the key signatures of aging, making it difficult to study the
interactions between AD genes, pathology, and aging with iPSC-derived cells. One recent study developed an
innovative approach to address this challenge by using Progerin, a protein associated with a premature aging
disorder. However, the Progerin gene, LMNA, is not normally expressed in human neurons or glia. In
contrast, another form of Progeria, Cockayne Syndrome (CS), which is caused by mutations that impair DNA
repair, leads to significant neurological defects. Furthermore, two of the genes that are mutated in CS, ERCC1
and ERCC5, are highly expressed in human microglia and their deletion in mice mimics key aspects of
microglial aging. Given these findings, we propose to test the hypothesis that deletion or mutations of ERCC1
and ERCC5 will produce changes in iPSC-derived microglia that mimic the effects of chronological aging and
impair the response of microglia to AD-associated insults. To achieve these goals, we have assembled a
multidisciplinary team who bring expertise in AD iPSC modeling, CRISPR-mediated gene deletion, and
microglial differentiation and analysis, RNA-sequencing and bioinformatics, and brain organoid culture systems
to test following three specific aims and hypotheses: Aim 1: Examine the impact of ERCC1/5 deletions and
mutations on iPSC-derived microglial function. We hypothesize that ERCC knockout and mutant microglia will
exhibit an age-associated `primed' activation state with impaired homestatic activity but exacerbated
inflammatory responses. Aim 2: Do ERCC1/5 deletions and mutations model the transcriptional effects of
aging observed in human brain-derived microglia? We hypothesize that deletion of these genes will produce
microglia that exhibit many of the transcriptional changes associated with natural brain aging. Aim 3: Defining
the intrinsic versus extrinsic effects of ERCC deletion on microglial aging with brain organoid cultures. We
hypothesis that both intrinsic and extrinsic signals influence microglial aging.

## Key facts

- **NIH application ID:** 9924476
- **Project number:** 5R01AG056303-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Mathew Mark Blurton-Jones
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $386,250
- **Award type:** 5
- **Project period:** 2017-07-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9924476

## Citation

> US National Institutes of Health, RePORTER application 9924476, Manipulating DNA repair enzymes to examine the interactions between aging and Alzheimers disease with iPSC-derived microglia (5R01AG056303-04). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9924476. Licensed CC0.

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