Mechanisms of Age-Related Microglial Impairment and Rejuvenation in Alzheimer's Disease

阿尔茨海默病中与年龄相关的小胶质细胞损伤和复兴的机制

• 批准号: 9608519
• 负责人: John Vincent Pluvinage
• 金额: $ 4.31万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-02 至 2021-08-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9608519
• 关键词: Abeta clearance; Affect; Affinity Chromatography; Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Anti-CD22; Apoptotic; Binding; Binding Proteins; Biochemical Genetics; Blocking Antibodies; Brain; Brain Diseases; Buffers; CD22 gene; CRISPR/Cas technology; Catalogs; Cause of Death; Cell Line; Cell surface; Cells; Clinical; Data; Deposition; Development; Disease; Elderly; Etiology; FDA approved; Failure; Functional disorder; Genes; Genetic; Health; Histology; Homeostasis; Immune; Immunoglobulins; Impaired cognition; Impairment; Incidence; Individual; Knock-out; Learning; Lectin; Mass Spectrum Analysis; Measures; Mediating; Memory; Microglia; Modality; Modification; Monoclonal Antibody Therapy; Mus; Nerve Degeneration; Neurodegenerative Disorders; Pathogenesis; Pathologic; Patients; Phagocytes; Phagocytosis; Phagocytosis Inhibition; Phenotype; Polysaccharides; Population; Predisposing Factor; Prevalence; Proteins; Receptors, Antigen, B-Cell; Regulation; Rejuvenation; Role; Sialic Acids; Signal Transduction; Signal Transduction Pathway; Synapses; Synaptosomes; Therapeutic; Tissues; United States; age related; aged; aging brain; base; cell motility; cell type; cognitive function; disorder risk; effective therapy; experimental study; feeding; fitness; genetic variant; immunoregulation; improved; macrophage; mouse model; normal aging; pathogen; prevent; receptor; sialic acid binding Ig-like lectin; sialic acid receptor; small molecule; therapeutic target; tool

Project Summary Age is the main risk factor for Alzheimer’s disease (AD), a neurodegenerative disorder rapidly increasing in both incidence and prevalence as the population becomes older. Unfortunately, AD is the only top ten cause of death with no effective treatments. Therefore, the development of disease-altering treatments for AD is an urgent and unmet need. Although the exact etiology of AD is unknown, microglia, the tissue-resident macrophages of the brain, have been implicated in disease pathogenesis based on the observation that genetic variants in several microglia-specific genes significantly alter disease risk. In the healthy brain, microglia maintain homeostasis through multiple modalities including phagocytic clearance of pathogens, apoptotic cells, and debris. In AD brains and age-matched clinically-unimpaired brains alike, microglia are dystrophic, hypo-motile, and burdened with lysosomal deposits indicative of impaired phagocytic degradation of debris. These findings suggest that the general decline in phagocytosis with age might underlie pathological neurodegeneration. However, the mechanisms of age-related microglial dysfunction are poorly understood. This proposal aims to elucidate the mechanisms of impaired microglial phagocytosis in the aging brain and to uncover therapeutic strategies to reverse this impairment in AD. Preliminary data suggest that cell-surface sialic acid, an immunomodulatory glycan modification, inhibits phagocytosis in aged microglia. Aim 1 combines biochemical and genetic tools to identify upstream and downstream signaling partners that transduce the anti- phagocytic effect of sialic acid on aged microglia. Aim 2 will evaluate the therapeutic potential of blocking the interaction between cell-surface sialic acid and its cognate receptor on microglia to promote phagocytosis and ameliorate cognitive decline in a mouse model of AD. These experiments will elucidate a mechanism of microglial dysfunction during normal aging with direct translational implications for patients with AD.

项目摘要 年龄是阿尔茨海默氏病（AD）的主要危险因素，神经退行性疾病迅速增加 随着人口年龄的增长，事件和患病率均已发生。不幸的是，广告是唯一的十大原因 没有有效治疗的死亡。因此，广告的改变疾病治疗是 紧急和未满足的需求。尽管AD的确切病因尚不清楚，小胶质细胞，但组织居民 基于观察到的，大脑的巨噬细胞已在疾病发病机理中暗示 几种小胶质细胞特异性基因的遗传变异显着改变了疾病的风险。在健康的大脑中 小胶质细胞通过多种方式维持体内稳态，包括病原体的吞噬清除， 凋亡细胞和碎屑。在广告大脑和年龄匹配的临床上无关的大脑中，小胶质细胞是 营养不良，运动不良，并用溶酶体沉积物燃烧，表明吞噬细胞降解受损 碎片。这些发现表明，随着年龄的增长，吞噬作用的总体下降可能是病理学的基础 神经变性。然而，与年龄相关的小胶质细胞功能障碍的机制知之甚少。 该建议旨在阐明衰老大脑中小胶质细胞增多症受损的机制 发现在AD中扭转这种障碍的治疗策略。初步数据表明细胞表面 唾液酸是一种免疫调节性聚糖修饰，抑制了老年小胶质细胞的吞噬作用。 AIM 1组合 生化和遗传工具，以识别上游和下游信号伴侣，可转导抗 唾液酸对老年小胶质细胞的吞噬作用。 AIM 2将评估阻止的治疗潜力 细胞表面唾液酸与其小胶质细胞上的同源受体之间的相互作用，以促进吞噬作用和 AD小鼠模型的认知能力下降。这些实验将阐明 正常衰老期间的小胶质细胞功能障碍对AD患者具有直接翻译的影响。