Methylglyoxal drives astrocyte senescence to mediate neurodegeneration in Alzheimer's disease

甲基乙二醛驱动星形胶质细胞衰老介导阿尔茨海默病的神经退行性变

基本信息

批准号：
10794538
负责人：
Pankaj Kapahi
金额：
$ 11.54万
依托单位：
BUCK INSTITUTE FOR RESEARCH ON AGING
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10794538
关键词：
Age Aging Alleles Alzheimer associated neurodegeneration Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Astrocytes Automobile Driving Brain Cell Aging Cells Coculture Techniques Combined Modality Therapy Dementia Drug Metabolic Detoxication Elderly Glycolysis Goals Human Induced pluripotent stem cell derived neurons Inflammation Inflammatory Knowledge Link Mediating Metabolic Metabolism Microglia Molecular Target Nerve Degeneration Neurodegenerative Disorders Neurons Pathway interactions Phenotype Proteomics Public Health Pyruvaldehyde Research Risk Reduction Role Testing Therapeutic Intervention Work induced pluripotent stem cell innovation mouse model mutant new therapeutic target novel novel strategies novel therapeutics parent grant pharmacologic senescence tau Proteins

项目摘要

PARENT GRANT: PROJECT SUMMARY Senescent astrocytes and microglia, which accumulate with age and in patients with AD, contribute to neurodegeneration. A major gap in our knowledge is understanding the mechanisms that lead to astrocyte senescence. Our long-term goal is to define the molecular targets and therapeutic interventions that slow aging by inhibiting senescence and to determine their impact on neurodegenerative diseases. The overall objective in this application is to: 1) define the mechanisms by which the glycolytic by-product methylglyoxal (MGO) drives astrocyte senescence and 2) enhance the detoxification of MGO to mitigate astrocyte senescence and neurodegeneration in models of AD. Our central hypothesis is that MGO induces senescence in astrocytes, which secrete pro-inflammatory senescence-associated secretory phenotype (SASP) factors that cause the neurodegeneration associated with dementia and AD. The rationale of our hypothesis is based partly on the fact that astrocytes are known to be the metabolic workhorses of the brain and undertake glycolysis to provide neurons with lactate. Consequently, astrocytes produce more MGO and show increased activity of the MGO detoxifying pathways. We observe that MGO, which enhances macromolecular damage, causes senescence. Thus, strategies to detoxify MGO can provide novel approaches to lowering the risk of AD and related neurodegeneration in the elderly. We will test the hypothesis by pursuing the following Specific Aims: 1). Determine the mechanisms by which MGO drives senescence in human iPSC derived astrocytes; 2) Determine the mechanisms by which senescent astrocytes cause neuronal damage; and 3) Determine the role of the Trpa1 pathway in modulating MGO-induced senescence and AD pathology in mouse models. We will use iPSC derived astrocytes to determine the mechanisms by which MGO mediates senescence. Furthermore, we will use proteomics to define the SASP of MGO-induced senescent astrocytes and determine the effect of the SASP on iPSC-derived neurons carrying wild type and mutant alleles of tau using co-cultures. We will genetically and pharmacologically manipulate Trpa1 to detoxify MGO to test its effects on senescence and associated neurodegeneration in two mouse models of AD. We will combine the treatments to detoxify MGO and eliminate senescent cells to determine if they are working through the same pathways to inhibit neurodegeneration. The proposed research is innovative because it will determine a novel function for MGO, an endogenous metabolite produced during glycolysis, in driving astrocytic senescence and, thus, neurodegeneration. A key significance of this work will help us understand the link between metabolism, inflammation, and neurodegeneration. It will also pave the way to developing novel therapies for treating Alzheimer’s and related dementias based on reducing the presence or activity of senescent cells and by lowering MGO.

父母赠款：项目摘要随着年龄的增长和AD患者积累的衰老星形胶质细胞和小胶质细胞，有助于神经变性。我们知识上的一个主要差距是了解导致星形胶质细胞的机制感应。我们的长期目标是定义放慢速度的分子靶标和治疗干预措施通过抑制感应并确定其对神经退行性疾病的影响而衰老。总体此应用中的目的是：1）定义糖酵解副产物甲基糖的机制（MGO）驱动星形胶质细胞的感应和2）增强MGO的排毒以减轻星形胶质细胞 AD模型中的感应和神经变性。我们的中心假设是MGO诱导着感应在星形胶质细胞中，分泌促炎感应相关的秘书表型（SASP）因素引起与痴呆和AD相关的神经变性。我们假设的理由是基于部分原因是星形胶质细胞被称为大脑的代谢主持人并进行糖酵解为乳酸提供神经元。因此，星形胶质细胞产生更多的MGO并显示出增加 MGO解毒途径的活性。我们观察到MGO增强了大分子损伤，引起感受。这是对MGO排毒的策略可以提供降低广告风险的新方法和古老的神经变性。我们将通过追求以下特定的特定来检验假设目标：1）。确定MGO在人IPSC衍生的星形胶质细胞中驱动感受的机制； 2）确定感觉星形细胞引起神经元损伤的机制； 3）确定角色在调节小鼠模型中MGO诱导的感应和AD病理学时，TRPA1途径的途径。我们将使用IPSC衍生的星形胶质细胞来确定MGO介导衰老的机制。此外，我们将使用蛋白质组学来定义MGO引起的感官星形胶质细胞的SASP并确定 SASP对使用共培养的野生型和突变等位基因的IPSC衍生神经元的影响。我们将一般和物理操纵TRPA1来排毒MGO以测试其对感应的影响和两个AD小鼠模型中的相关神经变性。我们将结合疗法以排毒 MGO并消除感觉细胞以确定它们是否正在通过相同的途径进行抑制神经变性。拟议的研究具有创新性，因为它将决定MGO的新功能，在糖酵解过程中产生的内源代谢产物，在驱动星形胶质细胞感应中，从而神经变性。这项工作的关键意义将有助于我们了解新陈代谢之间的联系炎症和神经变性。它还将为开发用于治疗的新型疗法铺平道路基于减少感觉细胞的存在或活性以及通过降低MGO。