Microglial dysfunction in brain aging and Alzheimer's disease

阿尔茨海默病(AD)会导致大脑的进行性退化，从而缓慢地破坏患者的 并对家庭和整个社会造成巨大的社会和经济负担。AS 据估计，在500万患有AD的美国人中，有20%是退伍军人，没有有效的治疗方法 目前，阿尔茨海默氏症协会预计，在未来20年内，患者数量将增加两倍。 AD的病因(S)在大多数情况下尚不清楚，但越来越多的证据表明，细胞清除和 蛋白质降解途径在疾病中可能受损，为治疗提供了潜在的新靶点 干预。事实上，在AD大脑中积聚成淀粉样斑块的Aβ的产生并不是 在散发性AD中增加，但现在基本上接受，相反，它的清除受到损害。一条路可以进去 Aβ可以通过小胶质细胞吞噬作用从大脑中清除。我们和其他人发现 在“正常”衰老的情况下，小胶质细胞变得炎症和吞噬功能缺陷，我们未发表的结果 表明年轻的系统性环境可以逆转其中一些功能障碍。年迈，功能失调 因此，小胶质细胞可能是包括阿尔茨海默病在内的年龄相关性神经退行性变的易感因素。然而， 与年龄相关的小胶质细胞功能障碍的机制还知之甚少。我们建议在这里调查 衰老脑内小胶质细胞吞噬功能受损的机制及治疗策略评价 在AD模型中逆转这种损害。无偏CRISPR-Cas9基因敲除筛选的初步数据 提示细胞表面唾液酸，一种免疫调节的糖链修饰，抑制老年人的吞噬功能 CD22是一种唾液酸受体，在小鼠和阿尔茨海默病患者的衰老小胶质细胞上表达上调， 调节这种抑制作用。基于可获得的出版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的CD22可以促进吞噬和 改善类AD疾病和神经退行性变。我们建议使用基因组和遗传工具来寻找 CD22的潜在调节剂功能确立CD22为年龄相关的小胶质细胞吞噬抑制物 并生成一个框架，用于理解这一功能的机制基础。此外，我们建议， 在表达突变人的转基因小鼠中用基因或使用单抗抑制CD22 淀粉样前体蛋白APP751Lon，Swe与10月龄左右发育中的疾病以及 在新发育的APPki小鼠小胶质细胞中转基因过表达CD22，表达 在内源性小鼠APP基因中没有突变的人类Aβ，并在18个月左右发展为疾病。 在建议的研究完成后，我们将有一个坚实的基础来理解CD22是如何调节的 小胶质细胞的吞噬作用，特别是衰老的小胶质细胞，以及靶向CD22是否具有治疗作用 治疗退伍军人及其亲人的AD样疾病的潜力。

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 We, and others, discovered that microglia become inflamed and defective in phagocytosis with “normal” aging, and our unpublished results show that a young systemic environment can reverse some of these dysfunctions.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.