Targeting CD22 to Restore Brain Homeostasis in Alzheimer's Disease

靶向 CD22 恢复阿尔茨海默氏病的大脑稳态

• 批准号: 10234488
• 负责人: TONY WYSS-CORAY
• 金额: $ 245.81万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10234488
• 关键词: Targeting; CD22; Restore; Brain; Homeostasis; Targeting; CD22; Restore; Brain; Homeostasis

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 aging and AD brains, microglia are dystrophic, hypo-motile, and burdened with lysosomal deposits indicative of impaired homeostatic function. These findings suggest that the general decline in microglial function 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 homeostasis in the aging brain and to uncover therapeutic strategies to reverse this impairment in AD. Our preliminary data suggest that CD22, a sialic-acid binding immunoglobulin-like lectin typically expressed on B-cells, inhibits phagocytosis in aged microglia and serves as a dominant regulator of microglial homeostasis. Aim 1 combines biochemical and genetic tools to identify upstream and downstream signaling partners that cooperate with CD22 to inhibit phagocytosis in microglia. Aim 2 will elucidate the role and regulation of microglial CD22 expression during development, aging, and AD. Aim 3 will define the neuronal response to restoration of microglial homeostasis upon CD22 blockade. Finally, Aim 4 will evaluate the therapeutic potential of blocking CD22 to ameliorate cognitive decline in mouse models of AD. These experiments will uncover a novel 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，发病率和流行率均已发生。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 大脑的巨噬细胞与疾病发病机理有关 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稳态，包括病原体的吞噬清除率， 凋亡细胞和碎屑。在衰老和广告大脑中，小胶质细胞是营养不良的，不动的，负担很大 溶酶体沉积物表明稳态功能受损。这些发现表明总体下降 在小胶质功能中，随着年龄的增长可能是病理神经退行性的基础。但是，机制 与年龄相关的小胶质功能障碍知之甚少。该建议旨在阐明 衰老大脑中的小胶质体稳态受损，并发现扭转这种策略的治疗策略 广告中的损害。我们的初步数据表明CD22是一种唾液酸结合的免疫球蛋白样凝集素 通常在B细胞上表达，抑制衰老小胶质细胞的吞噬作用，并作为主要调节剂 小胶质稳态。 AIM 1结合了生化和遗传工具，以识别上游和下游 与CD22合作以抑制小胶质细胞吞噬作用的信号伴侣。 AIM 2将阐明角色 以及在发育，衰老和AD期间的小胶质细胞CD22表达的调节。 AIM 3将定义 CD22阻断后小胶质体稳态恢复的神经元反应。最后，AIM 4将评估 在AD小鼠模型中阻止CD22减轻认知能力下降的治疗潜力。这些 实验将在正常衰老期间发现一种新型小胶质细胞功能障碍的新机制 对AD患者的翻译意义。