# Understanding the protective and neuroinflammatory role of human brain immune cells in Alzheimer Disease

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $1,530,945

## Abstract

PROJECT SUMMARY
Despite extensive clinical and genomic studies, the mechanisms of development and progression of
Alzheimer's disease (AD) remain elusive. Microglia and other myeloid origin cells (collectively called human
brain immune cells, or HBICs) have recently emerged as crucial players in the pathogenesis of AD. This is
supported through genetic association studies, where many of the common and rare risk loci affect genes that
are preferentially or selectively expressed in HBICs, emphasizing the pivotal role of the innate immune system
in AD. In addition, single cell RNA sequencing analysis in mouse models of AD has identified a microglia
subpopulation that is present at sites of neurodegeneration. It is unclear if HBICs assume a protective or
damaging role, but that might vary depending on the stage and progression of AD. Therefore, further analysis
of microglia and other immune cells purified from human brains is needed to understand the state of HBIC
activity in human AD at different stages of disease. As HBICs constitute a small proportion of total brain cells,
homogenate-based studies in human brain tissue are unlikely to capture the full spectrum of HBIC molecular
signatures, especially in light of the growing appreciation for the diversity of HBICs in the brain. The proposed
work addresses some of the limitations of previous research and is focused on: (1) cell type specific and single
cell studies in immune cells isolated from human brain tissue; and (2) a systematic study of the regulatory
effects of non-coding DNA on gene and protein expression, which is necessary given that the majority of
common risk variants are situated in non-coding regions of the genome. More specifically, our application is
uniquely designed to: (1) apply innovative genomic approaches and generate multi-omics data from HBICs
isolated from 300 donors, including whole genome sequencing, RNAseq, ATACseq, HiC chromosome
conformation capture and proteomics; (2) perform state-of-the-art single cell analysis that will allow us to
assess the diversity of HBIC subpopulations, as well as detect those that are associated with AD; (3) connect
AD risk loci with changes in the regulatory mechanisms of gene and protein expression in HBICs; and (4)
organize HBIC multiscale data in functional networks and identify key drivers for AD. Our overall hypothesis is
that HBIC subpopulations assume a neuroprotective role during aging and early stages of AD, but as disease
progresses, specific HBIC subpopulations transform to neuroinflammatory phenotype(s). This conversion is
partially driven by AD risk genetic variants, which affect regulatory mechanisms of genes that are key drivers of
neuroinflammatory HBIC subpopulations. Successful completion of the proposed studies will provide: (1) an
increased mechanistic understanding of dysfunction in AD risk loci; (2) prioritization of significant loci and
genes for future mechanistic studies; and (3) access to large-scale, multidimension...

## Key facts

- **NIH application ID:** 9866031
- **Project number:** 1R01AG065582-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** VAHRAM HAROUTUNIAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,530,945
- **Award type:** 1
- **Project period:** 2020-02-15 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9866031

## Citation

> US National Institutes of Health, RePORTER application 9866031, Understanding the protective and neuroinflammatory role of human brain immune cells in Alzheimer Disease (1R01AG065582-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9866031. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*