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

项目概要/摘要 衰老的星形胶质细胞和小胶质细胞随着年龄的增长以及在 AD 患者中积累，有助于 神经变性。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减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。总体目标在 该应用的目的是：1) 定义糖酵解副产物甲基乙二醛 (MGO) 驱动的机制 星形胶质细胞衰老和2)增强MGO的解毒作用以减轻星形胶质细胞衰老和 AD 模型中的神经退行性变。我们的中心假设是 MGO 会诱导星形胶质细胞衰老， 分泌促炎性衰老相关分泌表型（SASP）因子，导致 与痴呆和 AD 相关的神经退行性疾病。我们的假设的基本原理部分基于 事实上，星形胶质细胞被认为是大脑的代谢主力，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，并且 MGO 的活性增加 排毒途径。我们观察到 MGO 会增强大分子损伤，导致衰老。 因此，MGO 解毒策略可以提供降低 AD 及相关疾病风险的新方法。 老年人的神经退行性疾病。我们将通过追求以下具体目标来检验该假设：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Trpa1的作用 在小鼠模型中调节 MGO 诱导的衰老和 AD 病理学的途径。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 使用蛋白质组学来定义 MGO 诱导的衰老星形胶质细胞的 SASP 并确定 SASP 的效果 使用共培养物对携带野生型和突变型 tau 等位基因的 iPSC 衍生神经元进行研究。我们将从基因和 通过药理学操作 Trpa1 来解毒 MGO，以测试其对衰老和相关疾病的影响 两种 AD 小鼠模型中的神经退行性变。我们将结合治疗来解毒 MGO 并消除 衰老细胞以确定它们是否通过相同的途径抑制神经退行性变。的 拟议的研究具有创新性，因为它将确定 MGO（一种内源代谢物）的新功能 在糖酵解过程中产生，驱动星形胶质细胞衰老，从而导致神经退行性变。一个 这项工作的关键意义将帮助我们了解新陈代谢、炎症和疾病之间的联系。 神经变性。它还将为开发治疗阿尔茨海默病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降低 MGO 来治疗痴呆。

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.