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

通过破坏 LXRα 磷酸化来减轻神经炎症和阿尔茨海默病病理学

基本信息

批准号：
10460595
负责人：
MOSES VICTOR CHAO
金额：
$ 21.19万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10460595
关键词：
APP-PS1 Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Amyloid Anti-Inflammatory Agents Apolipoprotein E Attenuated Brain Cardiometabolic Disease Cell Line Cholesterol Homeostasis Chronic Cognitive Data Development Disease Disease Progression Etiology Exhibits Foundations Funding Gene Expression Genes Genetic Goals Hematologic Neoplasms Human Inflammation Inflammatory Inflammatory Response Innate Immune Response Intervention Knock-in Knock-in Mouse LXRalpha protein Ligands Link Lipids Liver X Receptor Measures Metabolic Metabolic Diseases Metabolism Microglia Mus Nuclear Receptors Pathway interactions Patients Phagocytes Phagocytosis Pharmacology Phosphorylation Pilot Projects Play Preventive Process Protein Isoforms Publishing Receptor Signaling Reporting Research Research Personnel Role Senile Plaques Serine Stimulus Testing Therapeutic Therapeutic Intervention Transgenic Mice United States National Institutes of Health Work amyloid peptide attenuation behavioral study casein kinase II genome wide association study immunoregulation inhibitor macrophage mouse model neuroinflammation novel strategies risk variant small molecule targeted treatment transcriptome transcriptome sequencing translational potential upstream kinase

项目摘要

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.

项目总结