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: 10633000
• 负责人: Pankaj Kapahi
• 金额: $ 8.01万
• 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/10633000
• 关键词: 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; 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; Lead; Link; Mediating; Metabolic; Metabolism; Microglia; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathway interactions; Patients; Pharmacology; Phenotype; Proteomics; Public Health; Pyruvaldehyde; Research; Role; Testing; Therapeutic Intervention; Work; base; induced pluripotent stem cell; innovation; molecular targeted therapies; mouse model; mutant; new therapeutic target; novel; novel strategies; novel therapeutics; parent grant; senescence; tau Proteins

PARENT GRANT: 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.

专利授权：项目总结/摘要 随着年龄的增长和AD患者体内衰老的星形胶质细胞和小胶质细胞的积累，有助于 神经变性我们知识的一个主要空白是理解导致星形胶质细胞 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。总体目标是 本申请的目的是：1）确定糖酵解副产物甲基乙二醛（MGO）驱动 星形胶质细胞衰老和2）增强MGO的解毒以减轻星形胶质细胞衰老， AD模型中的神经变性。我们的中心假设是MGO诱导星形胶质细胞衰老， 其分泌促炎性衰老相关分泌表型（SASP）因子，所述因子引起 与痴呆和AD相关的神经变性。我们假设的基本原理部分基于 事实上，已知星形胶质细胞是大脑的代谢主力，并进行糖酵解以提供 神经元与乳酸。因此，星形胶质细胞产生更多的MGO，并显示出MGO活性增加 解毒途径我们观察到，MGO，这增强了大分子的损伤，导致衰老。 因此，解毒MGO的策略可以提供降低AD和相关疾病风险的新方法。 老年人的神经退化我们将通过追求以下具体目标来检验假设：1）。 确定MGO驱动人iPSC衍生的星形胶质细胞衰老的机制; 2）确定 衰老星形胶质细胞引起神经元损伤的机制; 3）确定Trpa 1的作用 在调节小鼠模型中的MGO诱导的衰老和AD病理学中，我们将使用iPSC 衍生的星形胶质细胞，以确定MGO介导衰老的机制。此外，我们将 利用蛋白质组学来确定MGO诱导的衰老星形胶质细胞的SASP，并确定SASP的作用 使用共培养物对携带tau的野生型和突变体等位基因的iPSC衍生的神经元进行了研究。我们将从基因上， 药理学操纵Trpa 1对MGO进行解毒，以测试其对衰老和相关疾病的影响 在两种AD小鼠模型中的神经变性。我们将联合收割机的治疗，以解毒MGO和消除 衰老细胞，以确定它们是否通过相同的途径抑制神经变性。的 拟议的研究是创新的，因为它将确定一个新的功能MGO，一种内源性代谢物 在糖酵解过程中产生，驱动星形胶质细胞衰老，从而导致神经变性。一 这项工作的关键意义将有助于我们了解代谢，炎症和炎症之间的联系。 神经变性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。 基于减少衰老细胞的存在或活性以及通过降低MGO来治疗痴呆。