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.