# Attenuation of neuroinflammation and Alzheimer’s disease pathology by disrupting LXRα phosphorylation

> **NIH NIH R21** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $254,250

## Abstract

PROJECT SUMMARY
The goal of this proposal is to determine if LXRα phosphorylation at serine 196 (S196) is a possible target for
therapeutic intervention in Alzheimer's disease (AD). Our previous published studies demonstrated both in
cultured macrophages cell lines and in mouse models of cardiometabolic diseases that the non-phosphorylated
form of LXRα S196A reprograms the LXR-modulated transcriptome and produces a more anti-inflammatory
response. In addition, previous studies from others have shown that LXRα is a potential target for reducing
neuroinflammation, and AD pathology because genetic loss of LXRα in the APP/PS1 transgenic mouse model
of AD increased the number of amyloid plaques, while its activation attenuated the inflammatory response of
primary glial cultures to fibrillar amyloid peptide. As a majority of AD risk loci are in genes expressed most highly
in microglia, and that LXRα is expressed in both mouse and human microglia, we hypothesize that reducing
LXRα phosphorylation in microglia would restrain inflammation and diminish AD progression.
To test this we will develop a mouse model that harbors a microglia-specific LXRα S196A knockin in the context
of an AD-prone mouse (APP/PS1), and compare the number of AD plaques with those in wild-type littermate
controls. To examine effects of LXR
α S196 phosphorylation on the inflammatory gene expression, we will
generate primary glial cultures from wild-type and microglia-specific LXR
α S196A mice and measure their ability
to inhibit the inflammatory response to
fibrillar amyloid peptide. We will also perform RNA-seq of primary
microglia generated from WT and LXRα S196A mice in the absence and presence of fibrillar amyloid peptide to
reveal genes and pathways modulated by LXR
α S196 phosphorylation
that can be manipulated for preventive
and therapeutic purposes. Given that the LXRα inflammatory responses can be controlled by phosphorylation
we will also test whether pharmacological interventions that promote the non-phosphorylated form of the wild
type LXRα can protect APP/PS1 mice from AD pathology. Successful completion the aims will determine
whether LXRα phosphorylation represents a tractable target for the treatment of AD due to its ability to reduce
inflammatory gene expression in the brain.

## Key facts

- **NIH application ID:** 10285124
- **Project number:** 1R21AG073644-01
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** MOSES VICTOR CHAO
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $254,250
- **Award type:** 1
- **Project period:** 2021-08-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10285124

## Citation

> US National Institutes of Health, RePORTER application 10285124, Attenuation of neuroinflammation and Alzheimer’s disease pathology by disrupting LXRα phosphorylation (1R21AG073644-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10285124. Licensed CC0.

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