# Use of iPSC systems to define roles of microglial TREM2/DAP12 and CR3/DAP12 complexes and their genetic variants in specifying risk for late onset sporadic Alzheimer's disease

> **NIH NIH R01** · NEW YORK STEM CELL FOUNDATION · 2021 · $877,246

## Abstract

Project Summary
Microglia are strongly implicated in the pathogenesis of Alzheimer's disease (AD) including late onset sporadic
forms of the disease (LOAD). In addition to genetic studies that have identified microglial-enriched genetic
variants that influence AD risk, recent computational analysis of multi-scale omics data from hundreds of
human LOAD postmortem brains from our group and others in the NIA AMP-AD consortium suggest about one
third of the genes associated with risk are enriched or exclusively expressed in microglia. While neurons may
be the major cell type generating the toxic amyloid-beta peptide, the functional role of microglia in AD and their
interaction with other cell types in the brain to cause disease are still poorly understood and the etiology of AD
remains elusive. Key genetic variants in TYROBP/DAP12, TREM2, and APOE may have a functional disease
altering impact in distinct brain cell type or interact across cell types in the brain. In this application, we
propose to systematically identify and characterize the response of microglia to AD-associated insults in the
context of these variants. To study the role of these genes and their functional interaction in AD, we will first
generate a panel of CRISPR/Cas9-edited iPSC lines with isogenic mutations in TYROBP/DAP12, TREM2, and
APOE in all single and multi-allelic combinations and in the context of a single genetic background with clinical
and pathology confirmed LOAD. We will then generate hiPSC-derived neural co-culture systems and then
complex organoids from these isogenic lines to characterize the transcriptional and functional impact of key
genetic variants in single cell and cell-population-wide analyses. Single cell RNA sequencing data will be
generated to identify perturbation signatures for multi-allelic variants that will then be mapped to subtype
specific networks to build comprehensive signaling maps for each variant. Functional assays will be used to
build evidence for relevance to AD phenotypes. Our overall goal is to test the hypothesis that genetic variants
in TREM2, TYROBP/DAP12, and APOE will produce changes in iPSC-derived microglia that mimic the
response of microglia to AD-associated insults.

## Key facts

- **NIH application ID:** 10159833
- **Project number:** 5R01AG061894-04
- **Recipient organization:** NEW YORK STEM CELL FOUNDATION
- **Principal Investigator:** Valentina Fossati
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $877,246
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10159833

## Citation

> US National Institutes of Health, RePORTER application 10159833, Use of iPSC systems to define roles of microglial TREM2/DAP12 and CR3/DAP12 complexes and their genetic variants in specifying risk for late onset sporadic Alzheimer's disease (5R01AG061894-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10159833. Licensed CC0.

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