The Neuroprotective Role of PPAR-delta in Microglia

项目摘要/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。广告导致生活质量显著下降，并伴随着迅速增长 在艾滋病流行的情况下，迫切需要改进治疗方法。过氧化物酶体增殖物激活受体Delta 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， 研究表明，正常小鼠中枢神经系统(CNS)中PPARd功能的中断会导致 神经退行性变。PPARd激动剂目前也处于2a期临床试验中，用于治疗轻中度 广告。在所有的脑细胞中，小胶质细胞表达PPARd的水平最高；然而，PPARd的机制基础 小胶质细胞的活性仍未确定。小胶质细胞是中枢神经系统的常驻免疫细胞，一直以来 反复与AD的发病机制有关，因此了解PPARd在小胶质细胞中的作用将提供 洞察其治疗价值。 初步数据显示，PPARd可以抑制亨廷顿病患者大脑中的炎症， 帕金森氏病和自闭症模型小鼠。此外，初步的RNA测序数据显示 用PPARd激动剂KD3010处理野生型小鼠的小胶质细胞表明，PPARd激动剂导致 炎症基因(如IL-1b和SPP1)的下调以及几个AD相关基因的下调 小胶质细胞中的基因(如C1QA/C1QB、IL12b和TYROBP)。小胶质细胞已被证明具有异常 疾病环境中的表型。这些改变的表型在人类中被证明是细胞自主的。 诱导多能干细胞(IPSC)来源的小胶质样细胞(IMGL)，含有与AD相关的突变。 例如，APOE4小胶质细胞对β-淀粉样蛋白的摄取减少，缩短了 过程，并增加了促炎细胞因子的分泌。IMGL是人类强大的模型 小胶质细胞，因为它们在转录和表型上相似。 这一建议将揭示小胶质细胞中PPARd功能的机制基础，并询问 PPARd激动剂可以减弱AD背景下小胶质细胞的异常表型。我会先评估 神经保护靶点的PPARd反式激活是否依赖于与 转录共激活因子介体1和PU.1，这是AD的一个遗传风险因子，是否干扰 PPARd神经保护。然后，我将从含有AD风险等位基因(APOE4)的IPSC中获得iMGL以进行评估 PPARd能否减轻异常表型，侧重于细胞因子的分泌和吞噬功能 容量。了解PPARd在小胶质细胞中的作用及其激活如何影响AD患者的小胶质细胞 相关背景有可能进一步支持为什么PPARd激动症应该继续 作为治疗阿尔茨海默病的药物。

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.