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

• 批准号: 10285124
• 负责人: MOSES VICTOR CHAO
• 金额: $ 25.43万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10285124
• 关键词: APP-PS1; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' 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/antagonist; macrophage; mouse model; neuroinflammation; novel strategies; risk variant; small molecule; targeted treatment; transcriptome; transcriptome sequencing; upstream kinase

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 这项建议的目标是确定丝氨酸196位的lxrα磷酸化(S196)是否是 阿尔茨海默病(AD)的治疗干预。我们之前发表的研究表明，在 培养的巨噬细胞系和非磷酸化的心脏代谢性疾病的小鼠模型 LXRαS196A的形式对LXR调节的转录组重新编程，并产生更多抗炎 回应。此外，其他人之前的研究表明，lxrα是一个潜在的减少 APP/PS1转基因小鼠模型中LxRα基因缺失导致的神经炎症和AD病理 AD的激活可增加淀粉样斑块的数量，而激活则可减轻炎症反应。 原代胶质细胞培养为纤维淀粉样多肽。因为大多数AD风险基因座都是表达最高的基因 在小胶质细胞中，LXRα在小鼠和人小胶质细胞中都表达，我们假设减少 小胶质细胞中LXRα的磷酸化可抑制炎症反应，延缓AD进展。 为了测试这一点，我们将开发一种小鼠模型，该模型在上下文中包含小胶质细胞特异性LXRαS196A敲打信号 AD易感小鼠(APP/PS1)的斑块数量，并比较AD斑块的数量与野生型小鼠的斑块数量 控制。检查LXR的效果 αS196磷酸化对炎症基因表达的影响，我们将 从野生型和小胶质细胞特异性LXR获得原代胶质细胞培养 αS196A小鼠及其能力的测定 抑制炎症反应 纤维淀粉样多肽。我们还将执行初级的RNA-SEQ WT和LXRαS196A小鼠在没有和存在纤维淀粉样肽的情况下产生的小胶质细胞 揭示LXR调控的基因和途径 αS196磷酸化 可以被操控用于预防 和治疗目的。鉴于lxrα的炎症反应可以通过磷酸化来控制 我们还将测试促进野生非磷酸化形式的药物干预是否 LXR型α能保护APP/PS1小鼠免受AD病理的影响。成功完成的目标将决定 LXRα磷酸化是否是治疗AD的一个容易处理的靶点，因为它能够减少 炎性基因在大脑中的表达。