Microglial dysfunction in brain aging and Alzheimer's disease

大脑衰老和阿尔茨海默病中的小胶质细胞功能障碍

• 批准号: 9911972
• 负责人: TONY WYSS-CORAY
• 金额: --
• 依托单位: VETERANS ADMIN PALO ALTO HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9911972
• 关键词: Ablation; Acute; Affect; Age; Age-Months; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; American; Amyloid Beta A4 Precursor Protein; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloidosis; Antibodies; Binding; Brain; CD22 gene; CRISPR/Cas technology; Cell surface; Chronic; Community Health; Data; Degradation Pathway; Disease; Economic Burden; Elderly; Environment; FDA approved; Foundations; Functional disorder; Genetic; Genomics; Health Professional; Human; Human Amyloid Precursor Protein; Immunoglobulins; Impaired cognition; Impairment; In Vitro; Knock-in; Knock-out; Lead; Lectin; Measures; Mediating; Microglia; Modification; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mus; Myeloid Cells; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Pathologic; Pathway interactions; Patients; Phagocytes; Phagocytosis; Phagocytosis Inhibition; Polysaccharides; Predisposing Factor; Production; Publishing; Receptor Signaling; Receptors, Antigen, B-Cell; Regulation; Research; Role; Senile Plaques; Sialic Acids; Signal Transduction; Societies; Solid; Testing; Therapeutic; Therapeutic Intervention; Transgenic Mice; Transgenic Organisms; Veterans; Woman; abeta accumulation; age group; age related; age related neurodegeneration; aged; aging brain; aging population; base; cognitive ability; effective therapy; experimental study; family burden; hyperphosphorylated tau; immunoregulation; improved; in vivo; inhibitor/antagonist; loved ones; men; mouse model; mutant; new therapeutic target; normal aging; novel; overexpression; preclinical study; protein degradation; sialic acid binding Ig-like lectin; sialic acid receptor; single-cell RNA sequencing; social; statistics; success; tau-1; therapeutic target; tool; young adult

Alzheimer's disease (AD) produces a progressive degeneration of the brain that slowly destroys a victim's cognitive abilities and inflicts tremendous social and economic burden on families and society in general. As many as 20% of the estimated five million Americans with AD are Veterans, and with no effective treatments available currently, the Alzheimer's Association expects the number of patients will triple in the next 20 years. The cause(s) of AD is unknown in most cases but growing evidence suggests that cellular clearance and protein degradation pathways may be impaired in the disease providing potential new targets for therapeutic intervention. Indeed, the production of Aβ, which accumulates into amyloid plaques in AD brains, is not increased in sporadic AD but it is now largely accepted that, instead, its clearance is impaired. One way in which Aβ can be cleared from brains is through microglial phagocytosis. We, and others, discovered that microglia become inflamed and defective in phagocytosis with “normal” aging, and our unpublished results show that a young systemic environment can reverse some of these dysfunctions. Aged, dysfunctional microglia may thus be a predisposing factor for age-related neurodegeneration including AD. However, the mechanisms of age-related microglial dysfunction are poorly understood. We propose here to investigate the mechanisms of impaired microglial phagocytosis in the aging brain and to evaluate therapeutic strategies to reverse this impairment in models of AD. Preliminary data from an unbiased CRISPR-Cas9 knockout screen suggest that cell-surface sialic acid, an immunomodulatory glycan modification, inhibits phagocytosis in aged microglia, and that CD22, a sialic acid receptor upregulated on aged microglia in mice and in humans with AD, mediates this inhibition. Based on the available published background and our preliminary data we hypothesize that CD22 on microglia inhibits phagocytosis and that targeting CD22 can improve phagocytosis and ameliorate AD-like disease and neurodegeneration. We propose to use genomic and genetic tools to find potential modulators of CD22 function to establish CD22 as an age-related inhibitor of microglial phagocytosis and generate a framework for understanding the mechanistic basis of this function. We propose, furthermore, to inhibit CD22 genetically or using a monoclonal antibody in transgenic mice expressing mutant human amyloid precursor protein APP751Lon,Swe and developing disease around 10 months of age as well as overexpress CD22 transgenically in microglia in newly developed APP knock-in (APPki) mice, which express non-mutated human Aβ in the endogenous mouse APP gene and develop disease around 18 months of age. At completion of the proposed studies we will have a solid foundation of understanding how CD22 regulates phagocytosis in microglia, and aging microglia in particular, and whether targeting CD22 may have therapeutic potential for treating AD-like disease in Veterans and their loved ones.

阿尔茨海默病 (AD) 会导致大脑进行性退化，慢慢地破坏患者的大脑 认知能力，给家庭和整个社会造成巨大的社会和经济负担。作为 据估计，有 500 万患有 AD 的美国人中有 20% 是退伍军人，并且没有有效的治疗方法 目前，阿尔茨海默病协会预计患者数量将在未来 20 年内增加两倍。 在大多数情况下，AD 的病因尚不清楚，但越来越多的证据表明，细胞清除和 疾病中蛋白质降解途径可能受损，为治疗提供潜在的新靶点 干涉。事实上，Aβ 的产生会在 AD 大脑中积聚成淀粉样斑块，但它并不是 在散发性 AD 中增加，但现在人们普遍认为，其清除能力受到损害。一种方式进入 Aβ可以通过小胶质细胞的吞噬作用从大脑中清除。我们和其他人发现 随着“正常”衰老，小胶质细胞会发炎并出现吞噬功能缺陷，我们未发表的结果 表明年轻的系统环境可以逆转其中一些功能障碍。年老体弱、功能障碍 因此，小胶质细胞可能是包括 AD 在内的年龄相关神经变性的诱发因素。然而， 与年龄相关的小胶质细胞功能障碍的机制尚不清楚。我们在此建议调查 衰老大脑中小胶质细胞吞噬功能受损的机制并评估治疗策略 逆转 AD 模型中的这种损伤。来自无偏见 CRISPR-Cas9 敲除筛选的初步数据 表明细胞表面唾液酸（一种免疫调节聚糖修饰）抑制老年人的吞噬作用 小胶质细胞，以及 CD22（一种唾液酸受体，在患有 AD 的小鼠和人类的衰老小胶质细胞上上调， 介导这种抑制作用。根据现有的已发布背景和我们的初步数据，我们假设 小胶质细胞上的 CD22 抑制吞噬作用，靶向 CD22 可以提高吞噬作用 改善 AD 样疾病和神经退行性疾病。我们建议使用基因组和遗传工具来寻找 CD22 的潜在调节剂功能使 CD22 成为小胶质细胞吞噬作用的年龄相关抑制剂 并生成一个框架来理解该功能的机制基础。此外，我们建议， 通过基因抑制 CD22 或在表达突变人类的转基因小鼠中使用单克隆抗体 淀粉样蛋白前体蛋白 APP751Lon,Swe 和 10 个月左右出现疾病以及 在新开发的 APP 敲入 (APPki) 小鼠的小胶质细胞中转基因过度表达 CD22，该小鼠表达 小鼠内源性 APP 基因中未突变的人类 Aβ 并在 18 个月左右出现疾病。 完成拟议的研究后，我们将为了解 CD22 如何调节奠定坚实的基础 小胶质细胞，特别是衰老小胶质细胞的吞噬作用，以及靶向 CD22 是否可能具有治疗作用 治疗退伍军人及其亲人的 AD 类疾病的潜力。