# Elucidating the microglial mechanisms underlying sex-specific neuroinflammation in Alzheimer's Disease.

> **NIH NIH F31** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $26,924

## Abstract

Project Summary/Abstract
As the sixth leading cause of death in the U.S, Alzheimer’s Disease (AD) poses a significant health concern. Sex
differences are a hallmark component of AD, as two-thirds of AD patients are women. Global AD pathology is
also increased in female AD patients compared to male patients, providing evidence that sex differences in AD
extend beyond population dynamics into biological mechanisms. Both human genome-wide association studies
(GWAS) and mouse studies of AD have been used to unveil genetic risk factors; these findings have been
dominated by the apolipoprotein E4 (APOE4) allele (E4), which can endow up to a 12-fold increased risk of
developing AD. Notably, the E4 risk allele coupled with female sex leads to higher conversion rates to AD from
normal and mild cognitive impairment states, and significantly greater AD pathology in female than in male
carriers. APOE is largely produced by microglia, the chief innate immune cells of the brain, in the aging and
neurodegenerative brain. Furthermore, microglia expressing human E4 demonstrate heightened pro-
inflammatory response in the presence of tau pathology compared to all other APOE isoforms, suggesting a
potential neuroinflammatory mechanism involved in E4-risk of AD. These studies suggest that the primary
mechanism behind increased female susceptibility to AD may be due to sex-differences in neuroinflammatory
responses. However, the molecular mechanisms facilitating such sex differences in neuroinflammation remain
unknown. Using the Four Core Genotype mouse model, I will differentiate sex chromosomal from sex hormonal
effects in the neuroinflammatory response of aged mice. Our preliminary data shows that female mice exhibit
heightened pro-inflammatory cytokine response to lipopolysaccharide (LPS). Interestingly, we also show that XX
mice demonstrate exacerbation of the inflammatory response in the presence of either testes or ovaries. In this
proposal, we aim to further dissect the genetic mechanisms driving these XX versus XY differences in
neuroinflammation (Aim 1). Moreover, we will also use the Four Core Genotype model to investigate how sex
chromosomes and gonadal hormones alter neuroinflammation in response to tau pathology, by generating Four
Core Genotype and tauopathy mice expressing human E4 (Aim 2). Completing these aims will provide insights
on novel mechanisms regulating acute and chronic neuroinflammation while illuminating potential targets for
sex-specific therapeutics in Alzheimer’s Disease and other diseases implementing neuroinflammation.

## Key facts

- **NIH application ID:** 10232776
- **Project number:** 1F31AG072854-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Chloe Lopez-Lee
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $26,924
- **Award type:** 1
- **Project period:** 2021-04-08 → 2021-08-10

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10232776

## Citation

> US National Institutes of Health, RePORTER application 10232776, Elucidating the microglial mechanisms underlying sex-specific neuroinflammation in Alzheimer's Disease. (1F31AG072854-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10232776. Licensed CC0.

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