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

• 批准号: 10044138
• 负责人: Pankaj Kapahi
• 金额: $ 48.5万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10044138
• 关键词: 3xTg-AD mouse; Advanced Glycosylation End Products; Age; Aging; Alleles; Alzheimer associated neurodegeneration; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amino Acids; Astrocytes; Automobile Driving; Brain; Cell Aging; Cells; Cellular Stress Response; Cerebrospinal Fluid; Clinical; Coculture Techniques; Combined Modality Therapy; DNA; DNA Damage; Data; Dementia; Disease; Drug Metabolic Detoxication; Elderly; Excision; Failure; Glycolysis; Goals; Human; Incidence; Individual; Inflammaging; Inflammation; Inflammatory; Knowledge; Lactoylglutathione Lyase; Lead; Link; Lipids; Mediating; Mediator of activation protein; Metabolic; Metabolism; Microglia; Modeling; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nucleotides; Outcome; PARK7 gene; Parkinson Disease; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Proteins; Proteomics; Public Health; Pyruvaldehyde; Research; Risk Factors; Role; Signal Pathway; Stress; Tauopathies; Testing; Therapeutic; Therapeutic Intervention; Thioctic Acid; Tissues; Work; age related; base; brain tissue; cognitive function; genetic manipulation; improved; in vivo; induced pluripotent stem cell; innovation; knockout animal; molecular targeted therapies; mouse model; mutant; new therapeutic target; novel; novel strategies; novel therapeutics; presenilin-1; proteotoxicity; senescence; tau Proteins; therapeutic target

PROJECT SUMMARY / ABSTRACT 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.

项目摘要/摘要 衰老的星形胶质细胞和小胶质细胞，随着年龄的增长而积累，在AD患者中，有助于 神经退行性变。我们知识中的一个主要差距是理解导致星形胶质细胞的机制 衰老。我们的长期目标是确定延缓衰老的分子靶点和治疗干预措施 通过抑制衰老并确定其对神经退行性疾病的影响。年的总体目标 这一应用是为了：1)确定糖酵解副产物甲基乙二醛(MGO)驱动的机制 2)增强氧化镁的解毒作用，延缓星形胶质细胞的衰老。 阿尔茨海默病模型中的神经变性。我们的中心假设是氧化镁诱导星形胶质细胞衰老， 分泌促炎症衰老相关的分泌表型(SASP)因子，导致 与痴呆症和阿尔茨海默病相关的神经变性。我们假设的基本原理部分是基于 已知星形胶质细胞是大脑的新陈代谢主力，并进行糖酵解以提供 含乳酸的神经元。因此，星形胶质细胞产生更多的MGO，并表现出MGO的活性增加 排毒途径。我们观察到，增强大分子损伤的氧化镁会导致衰老。 因此，MGO的解毒策略可以提供新的方法来降低AD和相关的风险 老年人的神经退行性变。我们将通过追求以下具体目标来检验这一假设：1)。 确定MGO促进人iPSC来源的星形胶质细胞衰老的机制；2)确定 衰老的星形胶质细胞引起神经元损伤的机制；以及3)决定TRPA1的作用 氧化镁致小鼠衰老和阿尔茨海默病病理调控途径。我们将使用IPSC 以确定氧化镁调节衰老的机制。此外，我们还将 用蛋白质组学方法确定氧化镁诱导衰老星形胶质细胞的SASP并确定SASP的作用 在携带tau野生型和突变型等位基因的ipsc来源的神经元上进行共培养。我们将从基因上和 药理操作TRPA1解毒MGO以检测其对衰老及相关基因的影响 阿尔茨海默病两种小鼠模型的神经退行性变。我们将结合治疗MGO解毒和消除 以确定它们是否通过相同的途径抑制神经退化。这个 拟议的研究具有创新性，因为它将确定内源性代谢物MGO的新功能 在糖酵解过程中产生，促进星形胶质细胞衰老，从而导致神经退化。一个 这项工作的关键意义将有助于我们理解新陈代谢、炎症和 神经退行性变。它还将为开发治疗阿尔茨海默氏症和相关疾病的新疗法铺平道路 痴呆症的基础是减少衰老细胞的存在或活性，并通过降低MGO。