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: 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
• 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' 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; macrophage; mouse model; neuroinflammation; novel strategies; risk variant; small molecule; targeted treatment; transcriptome; transcriptome sequencing; translational potential; 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.

项目摘要 该提案的目标是确定LXRα在丝氨酸196（S196）的磷酸化是否是LXRα表达的可能靶点。 阿尔茨海默病（AD）的治疗干预。我们先前发表的研究表明， 培养的巨噬细胞细胞系和心脏代谢疾病的小鼠模型中， LXRα S196 A的形式重新编程LXR调节的转录组，并产生更强的抗炎作用。 反应此外，其他人先前的研究表明，LXRα是降低 神经炎症和AD病理学，因为APP/PS1转基因小鼠模型中LXRα的遗传缺失 AD增加了淀粉样斑块的数量，而其激活则减弱了AD的炎症反应。 原代胶质细胞培养物转化为纤维状淀粉样肽。由于大多数AD风险位点位于表达最高的基因中， 在小胶质细胞中，LXRα在小鼠和人类小胶质细胞中都有表达，我们假设减少LXRα表达， 小胶质细胞中LXRα的磷酸化可抑制炎症反应，减缓AD的进展。 为了测试这一点，我们将开发一种小鼠模型，该模型在背景下携带小胶质细胞特异性LXRα S196 A敲入。 AD易感小鼠（APP/PS1）的AD斑块数量，并与野生型同窝小鼠的AD斑块数量进行比较 对照检查LXR的影响 α S196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产生原代胶质细胞培养物 α S196 A小鼠并测量其能力 抑制炎症反应， 纤维状淀粉样肽我们还将进行初级RNA测序 WT和LXRα S196 A小鼠在存在和不存在纤维状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 α S196磷酸化 它可以被用来预防 和治疗目的。鉴于LXRα炎症反应可以通过磷酸化来控制， 我们还将测试促进野生型非磷酸化形式的药物干预是否 LXRα对APP/PS 1小鼠AD有保护作用。成功完成目标将决定 LXRα磷酸化是否是治疗AD的一个易处理的靶点，因为它能够减少 大脑中的炎症基因表达。