# Investigating the convergence of AD genetics on lipid metabolism and microglia regulation

> **NIH NIH R21** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $431,216

## Abstract

PROJECT SUMMARY
 Genetic studies in Alzheimer’s disease (AD) have clearly indicated a role for microglia, the innate immune
cells of the CNS, in susceptibility to disease. Moreover, microglia are also implicated in lipid metabolism as a
key component of disease mechanism. Microglia are the resident immune cells of the CNS, and are therefore
the primary responders to pathogens. More and more correlation studies implicate pathogens in AD
pathogenesis or progression. However, the association between genetic alterations specific to microglia, toll-like
receptor (TLR) signaling and lipid homeostasis in AD has not been explored in depth. We hypothesize that there
is an interaction between the natural function of the genetically associated microglial proteins, lipids and TLR
stimulation, the basic biology of which has not been fully elucidated in microglia, the innate immune cells that
exist in a lipid rich environment.
 Among the many factors involved in the regulation of pathogen response pathways, the lipid composition
of microglia has been shown to contribute significantly to the regulation of inflammatory signaling. Specifically,
cholesterol and sphingomyelin levels have been observed to modulate the expression and distribution of
microglia receptors and their downstream targets. We propose that microglia AD risk variants result in
disturbances in the regulation of sphingolipid and cholesterol, that in turn, cause the dysregulation of
TLR responses and inflammatory phenotypes. We will investigate this hypothesis by examining the effects
of microglia AD susceptibility alleles on sphingolipid regulation and lipid raft turnover in a cell culture microglial
model. We will also assess the role of sphingolipids in the regulation of microglial signaling via TLR and
genetically associated proteins in our microglia model.
 Results from this proposal will help understand the crosstalk between genetics, TLR-regulation and
sphingolipid metabolism and underlying mechanisms by which a microglia induces inflammation through
modulation of its membrane in the context of AD.

## Key facts

- **NIH application ID:** 10288338
- **Project number:** 1R21AG073882-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Estela Area Gomez
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $431,216
- **Award type:** 1
- **Project period:** 2021-08-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10288338

## Citation

> US National Institutes of Health, RePORTER application 10288338, Investigating the convergence of AD genetics on lipid metabolism and microglia regulation (1R21AG073882-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10288338. Licensed CC0.

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