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.

项目总结/摘要 阿尔茨海默病（AD）是一种以进行性记忆丧失为特征的神经退行性疾病 和认知障碍。AD导致生活质量显著降低，并且随着AD的快速增长， 然而，由于疾病的流行，迫切需要改进的疗法。过氧化物酶体激活受体δ PPARd是一种配体激活的转录因子，已成为神经保护的潜在靶点。 PPARd激动作用已显示改善神经变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功能的破坏已经显示出引起 神经变性PPARd激动作用目前也在用于治疗轻度至中度的帕金森病的2a期临床试验中。 AD.在所有脑细胞中，小胶质细胞表达PPARd最高;然而，PPARd的机制基础 小胶质细胞的活性仍然不确定。小胶质细胞是CNS的常驻免疫细胞， PPARd在AD发病机制中的作用，因此了解PPARd在小胶质细胞中的作用将为我们提供 了解它的治疗价值。 初步数据显示，PPARd可以抑制亨廷顿病患者大脑中的炎症， 帕金森病和tau蛋白病模型小鼠。此外，初步的RNA测序数据分离 来自用PPARd激动剂KD 3010处理的野生型小鼠的小胶质细胞显示，PPARd激动导致 炎症基因（如IL-1b和SPP 1）的下调以及几种AD相关基因的下调， 小胶质细胞中的基因（例如C1 QA/C1 QB、IL 12 b和TYROBP）。小胶质细胞已经显示出异常的 在疾病环境中的表型。这些改变的表型已被证明是细胞自主在人类 诱导多能干细胞（iPSC）衍生的小胶质细胞样细胞（iMGL），其具有与AD相关的突变。 例如，已经显示APOE 4小胶质细胞表现出减少的β-淀粉样蛋白摄取，缩短了APOE 4小胶质细胞对β-淀粉样蛋白的摄取。 过程，并增加促炎细胞因子分泌。iMGL是人类的强大模型 小胶质细胞，因为它们在转录和表型上相似。 该提案将揭示PPARd在小胶质细胞中功能的机制基础，并询问是否 PPARd激动可以减弱AD背景下小胶质细胞中观察到的异常表型。我先评估一下 PPARd反式激活神经保护靶点是否依赖于与 转录辅激活因子介体1和PU.1是否是AD的遗传风险因子， PPARd神经保护。然后，我将从携带AD风险等位基因（APOE 4）的iPSC中获得iMGL，以评估 PPARd是否可以减轻异常表型，重点关注细胞因子分泌和吞噬功能， 容量了解PPARd在小胶质细胞中的作用及其激活如何影响AD中的小胶质细胞， 相关的环境有可能提供进一步的支持，为什么PPARd激动作用应该继续 作为AD的治疗药物。