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

New York University School Of Medicine, New York NY

Investigators

Abstract

PROJECT SUMMARY The goal of this proposal is to determine if LXR? 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 LXR? S196A reprograms the LXR-modulated transcriptome and produces a more anti-inflammatory response. In addition, previous studies from others have shown that LXR? is a potential target for reducing neuroinflammation, and AD pathology because genetic loss of LXR? 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 LXR? is expressed in both mouse and human microglia, we hypothesize that reducing LXR? phosphorylation in microglia would restrain inflammation and diminish AD progression. To test this we will develop a mouse model that harbors a microglia-specific LXR? 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 ? S196 phosphorylation on the inflammatory gene expression, we will generate primary glial cultures from wild-type and microglia-specific LXR ? 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 LXR? S196A mice in the absence and presence of fibrillar amyloid peptide to reveal genes and pathways modulated by LXR ? S196 phosphorylation that can be manipulated for preventive and therapeutic purposes. Given that the LXR? inflammatory responses can be controlled by phosphorylation we will also test whether pharmacological interventions that promote the non-phosphorylated form of the wild type LXR? can protect APP/PS1 mice from AD pathology. Successful completion the aims will determine whether LXR? phosphorylation represents a tractable target for the treatment of AD due to its ability to reduce inflammatory gene expression in the brain.