Assessing cell specific proteomes in the presence and absence of C5a complement signaling in Alzheimer's disease models

评估阿尔茨海默病模型中存在和不存在 C5a 补体信号传导的细胞特异性蛋白质组

• 批准号: 10046003
• 负责人: Robert C Spitale
• 金额: $ 22.84万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 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 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046003
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid beta-Protein; Animal Model; Animals; Astrocytes; BRAIN initiative; Binding; Biochemical; Brain; Cells; Chemicals; Cognitive; Communities; Complement; Complement 5a; Complement Activation; Data; Development; Disease Progression; Elderly; Gene Expression; Gene Expression Alteration; Genetic; Goals; Image; Immunohistochemistry; Impaired cognition; In Vitro; Incidence; Inflammation; Inflammatory; Innate Immune System; Knowledge; Label; Late Onset Alzheimer Disease; Mass Spectrum Analysis; Methods; Microglia; Mus; Neuraxis; Neurobiology; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Pathogenesis; Pathologic; Pattern; Phenotype; Production; Proteins; Proteome; Protocols documentation; RNA; Reagent; Role; Signal Transduction; Technology; United States National Institutes of Health; Validation; brain tissue; cell type; design; immune activation; innate immune mechanisms; mouse model; nervous system disorder; novel; preservation; prevent; programs; protein expression; protein profiling; protein purification; receptor; repaired; response; small molecule; targeted treatment; tool

Project Summary. Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease of the elderly. The complement cascade, a powerful effector mechanism of the innate immune system that can be directly activated by fibrillar Aβ, is implicated as a player in this inflammatory scenario. In brain, expression of most complement components increases during aging and further increases in AD patients and animal models of AD, consistent with a role for complement immune activation in progression of the disease. Complement activation fragment C5a has been a major focus, as inhibition of its proinflammatory receptor, C5aR1, leads to less activation of microglia and astrocytes, preservation of neuronal complexity and reduction of cognitive loss in AD models. These critical observations strongly suggest C5a binding to its receptor C5aR1 initiates cellular activation leading to changes in protein expression in microglia and astrocytes, which result in pathological phenotypes and disease progression. The primary goal of this proposal is to systemically understand alterations in cell-specific protein expression that result from signaling via C5a-C5aR1 in the context of Alzheimer’s disease. Specifically, this will extend our knowledge of induction of specific RNAs to production of the proteins, and the contribution of each cell type to those functional proteins, that ultimately accelerate pathogenesis and neuronal dysfunction in Alzheimer’s disease models.

项目摘要。 阿尔茨海默病（AD）是老年人最常见的神经退行性疾病。补语 级联，先天免疫系统的强大效应机制，可以直接被纤维激活 Aβ 是这种炎症场景中的一个参与者。在大脑中，大多数补体成分的表达 随着年龄的增长而增加，并且在 AD 患者和 AD 动物模型中进一步增加，这与 疾病进展过程中补体免疫激活。补体激活片段 C5a 主要关注点是，抑制其促炎受体 C5aR1 会导致小胶质细胞的激活减少， 星形胶质细胞，保留神经元复杂性并减少 AD 模型中的认知丧失。这些关键的 观察结果强烈表明 C5a 与其受体 C5aR1 结合启动细胞激活，导致变化 小胶质细胞和星形胶质细胞的蛋白质表达，导致病理表型和疾病 进展。该提案的主要目标是系统地了解细胞特异性蛋白质的变化 在阿尔茨海默病中，C5a-C5aR1 信号传导导致的表达。具体来说，这将 将我们对诱导特定 RNA 的知识扩展到蛋白质的生产，以及每个 RNA 的贡献 细胞类型到那些功能蛋白，最终加速发病机制和神经元功能障碍 阿尔茨海默病模型。