The Neuroprotective Role of PPAR-delta in Microglia

PPAR-δ 在小胶质细胞中的神经保护作用

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease risk Alzheimer&apos s disease therapeutic Alzheimer&apos 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

项目摘要

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.