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

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.

项目概要 年龄是阿尔茨海默病 (AD) 的主要危险因素，阿尔茨海默病是一种神经退行性疾病，在全球范围内迅速增加 随着人口老龄化，发病率和患病率都会增加。不幸的是，AD 是唯一的十大原因 没有有效的治疗方法而死亡。因此，开发改变AD疾病的治疗方法是一个重要的课题。 紧急且未满足的需求。尽管 AD 的确切病因尚不清楚，但小胶质细胞（组织驻留细胞） 根据以下观察，大脑巨噬细胞与疾病发病机制有关 几个小胶质细胞特异性基因的遗传变异显着改变疾病风险。在健康的大脑中， 小胶质细胞通过多种方式维持体内平衡，包括吞噬清除病原体， 凋亡细胞和碎片。在衰老和 AD 大脑中，小胶质细胞营养不良、运动能力低下，并承受着 溶酶体沉积表明体内平衡功能受损。这些发现表明总体下降 随着年龄的增长，小胶质细胞功能的改变可能是病理性神经变性的基础。然而，其机制 与年龄相关的小胶质细胞功能障碍尚不清楚。该提案旨在阐明其机制 衰老大脑中小胶质细胞稳态受损，并发现扭转这种情况的治疗策略 AD 损伤。我们的初步数据表明 CD22，一种唾液酸结合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 小胶质细胞稳态。目标 1 结合生化和遗传工具来识别上游和下游 与 CD22 配合抑制小胶质细胞吞噬作用的信号传导伙伴。目标 2 将阐明其作用 以及发育、衰老和 AD 过程中小胶质细胞 CD22 表达的调节。目标 3 将定义 CD22 阻断后小胶质细胞稳态恢复的神经元反应。最后，目标4将评估 阻断 CD22 改善 AD 小鼠模型认知能力下降的治疗潜力。这些 实验将揭示正常衰老过程中小胶质细胞功能障碍的新机制 对 AD 患者的转化意义。