The Neuroprotective Role of PPAR-delta in Microglia

PPAR-δ 在小胶质细胞中的神经保护作用

• 批准号: 10751623
• 负责人: Jacob Sahag Deyell
• 金额: $ 5.27万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751623
• 关键词: Adipocytes; Affect; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer' s disease therapeutic; Alzheimer' s disease therapy; Amyloid beta-Protein; Anti-Inflammatory Agents; Attenuated; Brain; Cell model; Cells; Central Nervous System; Clinical Treatment; Clinical Trials; Data; Dependence; Disease; Down-Regulation; Exhibits; Experimental Autoimmune Encephalomyelitis; Exposure to; Family; Gene Activation; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Homeostasis; Human; Huntington Disease; Immune; Impaired cognition; Inflammation; Inflammatory; Ligands; Light; Link; Mediator; Membrane; Memory Loss; Microglia; Modeling; Mus; Mutation; Nature; Nerve Degeneration; Neurodegenerative Disorders; PPAR delta; PTEN gene; Parkinson Disease; Pathogenesis; Peroxisome Proliferator-Activated Receptors; Phagocytes; Phase; Phenotype; Play; Pluripotent Stem Cells; Prevalence; Process; Production; Quality of life; Research; Role; SIRT1 gene; TYROBP gene; Tauopathies; Testing; Therapeutic; Transactivation; Transcription Coactivator; Transcriptional Regulation; Translating; Wild Type Mouse; Work; apolipoprotein E-4; brain cell; cytokine; disease phenotype; genetic risk factor; improved; in vitro Model; in vivo; induced pluripotent stem cell; inflammatory marker; insight; member; mouse model; neuroinflammation; neuroprotection; novel therapeutic intervention; risk variant; tau Proteins; therapeutic target; transcription factor; transcriptome sequencing; uptake

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and cognitive impairment. AD leads to a significant reduction in quality of life, and with a rapidly growing prevalence, there is a dire need for improved therapies. Peroxisome Proliferator-Activated Receptor delta (PPARd) is a ligand activated transcription factor that has emerged as a potential target for neuroprotection. PPARd agonism has been shown to improve disease phenotypes in neurodegenerative disease model mice, and disruption of PPARd function in the central nervous system (CNS) of normal mice has been shown to elicit neurodegeneration. PPARd agonism is also currently in a Phase 2a clinical trial for treatment of mild-to-moderate AD. Of all the brain cells, microglia express PPARd most highly; however, the mechanistic basis of PPARd activity in microglia remains undefined. Microglia are the resident immune cells of the CNS and have been repeatedly implicated in the pathogenesis of AD, so understanding the role of PPARd in microglia will provide insight into its therapeutic value. Preliminary data reveals that PPARd can suppress inflammation in the brains of Huntington’s disease, Parkinson’s disease and tauopathy model mice. Additionally, preliminary RNA-sequencing data on isolated microglia from wild-type mice treated with the PPARd agonist KD3010 shows that PPARd agonism leads to downregulation of inflammatory genes (e.g. Il-1b and SPP1) as well as the downregulation of several AD relevant genes in microglia (e.g. C1QA/C1QB, IL12b and TYROBP). Microglia have been shown to take on aberrant phenotypes in disease settings. These altered phenotypes have been shown to be cell-autonomous in human induced pluripotent stem cell (iPSC)-derived microglia like cells (iMGLs) that harbor mutations relevant to AD. For example, APOE4 microglia have been shown to exhibit reduced uptake of beta-amyloid, have shortened processes, and have increased pro-inflammatory cytokine secretion. iMGLs are powerful models for human microglia, as they are transcriptionally and phenotypically similar. This proposal will uncover the mechanistic basis of PPARd function in microglia and interrogate whether PPARd agonism can attenuate the aberrant phenotypes seen in microglia in the context of AD. I will first assess whether PPARd transactivation of neuroprotective targets is dependent upon phase separation with the transcriptional coactivator Mediator 1 and whether PU.1, which is a genetic risk factor for AD, interferes with PPARd neuroprotection. I will then derive iMGLs from iPSCs that harbor an AD risk allele (APOE4) to assess whether PPARd can attenuate the abnormal phenotypes, focusing on cytokine secretion and phagocytic capacity. Understanding the role that PPARd plays in microglia and how its activation affects microglia in an AD- relevant setting has the potential to provide further support as to why PPARd agonism should continue to be pursued as a therapeutic for AD.

项目摘要/摘要 阿尔茨海默氏病（AD）是一种神经退行性疾病，其特征是进行性记忆丧失 和认知障碍。广告可显着降低生活质量，并迅速增长 患病率迫切需要改善疗法。过氧化物体增生剂激活受体三角洲 （PPARD）是配体激活的转录因子，已成为神经保护的潜在靶标。 PPARD激动剂已被证明可以改善神经退行性疾病模型小鼠的疾病表型， 正常小鼠中枢神经系统（CNS）中PPARD功能的破坏已被证明引起 神经变性。当前，PPARD激动剂也在2A期临床试验中，用于治疗轻度至中度 广告。在所有脑细胞中，小胶质细胞表达PPARD最高。但是，ppard的机械基础 小胶质细胞的活性仍然不确定。小胶质细胞是中枢神经系统的居民，已经 反复与AD的发病机理有关，因此了解PPARD在小胶质细胞中的作用将提供 深入了解其治疗价值。 初步数据表明，PPARD可以抑制亨廷顿氏病的注射， 帕金森氏病和陶氏病模型小鼠。此外，关于孤立的RNA测序数据 用PPARD激动剂KD3010处理的野生型小鼠的小胶质细胞表明，PPARD激动剂会导致 炎症基因（例如IL-1B和SPP1）的下调以及几种AD相关的下调 小胶质细胞中的基因（例如C1QA/C1QB，IL12B和TyroBP）。已证明小胶质细胞发生异常 疾病环境中的表型。这些改变的表型已被证明是人类的细胞自主 诱导多能干细胞（IPSC）衍生的小胶质细胞（IMGL）具有与AD相关的突变。 例如，已证明APOE4小胶质细胞暴露于β-淀粉样蛋白的摄取减少，已缩短 过程，并增加了促炎性细胞因子分泌。 IMGL是人类的强大模型 小胶质细胞在转录和表型上是相似的。 该建议将揭示小胶质细胞中PPARD功能的机理基础，并询问是否是否 PPARD激动剂可以减弱在AD背景下在小胶质细胞中看到的异常表型。我将首先评估 神经保护靶标的PPARD是否取决于与相分离 转录共激活因子1以及PU.1是否是AD的遗传风险因素，是否会干扰 PPARD神经保护。然后，我将从具有广告风险等位基因（APOE4）的IPSC中得出IMGL来评估 PPARD是否可以减弱异常表型，重点是细胞因子分泌和吞噬细胞 容量。了解PPARD在小胶质细胞中的作用以及其激活如何影响AD-中的小胶质细胞 相关环境有可能提供进一步的支持，即为什么应该继续ppard agonism 作为广告疗法追求。