# Implicating novel microglial mechanisms of late-onset Alzheimer's disease with variant-to-gene mapping methods

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2021 · $46,036

## Abstract

ABSTRACT
 Late-onset Alzheimer’s disease (LOAD) is the most common neurodegenerative disease among the
elderly population, affecting nearly 6 million US adults over the age of 65. Despite being the 6th leading cause
of death in the US, there are still no effective therapies that can slow or halt disease progression. The
prevailing molecular feature that differentiates LOAD from other types of neurodegenerative dementia is the
extracellular aggregation of inappropriately cleaved amyloid-b protein plaques
(Ab1-42) in the brain. In response
to Ab1-42 production, microglia, the resident macrophages of the central nervous system (CNS) activate and
migrate to the site of plaque accumulation, and then break down and phagocytose the plaques, while also
secreting pro-inflammatory cytokines to stimulate the innate immune response. Persistent production of these
cytokines reduces microglial ability to clear Ab1-42 in a negative feedback loop, and results increased formation
of interfibrillary tangles in the neurons that exacerbates neurodegeneration. Large genome-wide association
studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) that associate with LOAD and
reside near genes with known rare coding variants that affect microglial function, further emphasizing the
importance of microglia in LOAD pathology. However, while GWAS has successfully identified numerous
genetic loci associated with LOAD, it cannot directly identify the causal SNP implicated by these loci, as a
GWAS sentinel SNP is representative of an entire haplotype of SNPs. Additionally, the majority of these
GWAS SNPs lie within non-coding regions of the genome, and may not necessarily implicate the nearest gene
as causal. Instead, these SNPs likely regulate the expression of LOAD-associated genes by modulating the
activity of distal regulatory elements, such as enhancers, which in turn regulate LOAD gene expression.
Therefore, I hypothesize that LOAD GWAS SNPs contribute to the dysregulated inflammation and
phagocytosis in the brains of LOAD patients by altering the regulatory activity of microglial enhancers and the
expression of their linked effector genes. In Aim 1, I will utilize a “variant-to-gene mapping” approach to identify
putatively causal LOAD GWAS SNPs in the microglia by identifying SNPs that lie within open chromatin, are
enriched in marks of active enhancers, and function as expression quantitative trait loci in microglial cell
models. I will validate the activity of these enhancers through luciferase assays in the microglial cell models,
and I will also identify the likely effector genes whose expression are modulated by these enhancers through
our lab’s promoter-focused Capture-C assay. In Aim 2, I will functionally validate the phenotype conferred by
LOAD-associated microglial enhancers by knocking out these enhancers in microglial cell models using
CRISPR, and then assessing how these knockouts impact global gene expression, inflammation, and
phagoc...

## Key facts

- **NIH application ID:** 10312478
- **Project number:** 1F31AG074532-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** ELIZABETH Anne BURTON
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 1
- **Project period:** 2021-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10312478

## Citation

> US National Institutes of Health, RePORTER application 10312478, Implicating novel microglial mechanisms of late-onset Alzheimer's disease with variant-to-gene mapping methods (1F31AG074532-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10312478. Licensed CC0.

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