Targeting CD22 to Restore Brain Homeostasis in Alzheimer's Disease

项目摘要 年龄是阿尔茨海默病（AD）的主要危险因素，AD是一种在老年人中迅速增加的神经退行性疾病。 随着人口老龄化，发病率和患病率都有所下降。不幸的是，AD是唯一的十大原因， 没有有效治疗的死亡。因此，开发AD的改变疾病的治疗方法是一项重要的研究。 迫切和未满足的需求。虽然AD的确切病因尚不清楚，但组织驻留的小胶质细胞 脑的巨噬细胞与疾病的发病机制有关， 几个小胶质细胞特异性基因的遗传变异显著改变疾病风险。在健康的大脑中， 小胶质细胞通过多种方式维持体内平衡，包括病原体的吞噬清除， 凋亡细胞和碎片。在衰老和AD脑中，小胶质细胞是营养不良的，运动性减退的，并且负担着许多疾病。 溶酶体沉积物，表明体内平衡功能受损。这些发现表明， 小胶质细胞功能随年龄的变化可能是病理性神经变性的基础。然而， 年龄相关的小胶质细胞功能障碍知之甚少。该提案旨在阐明 受损的小胶质细胞稳态在老化的大脑，并揭示治疗策略，以扭转这一点 在AD中受损。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，抑制老年小胶质细胞的吞噬作用，并作为一种主要的调节因子， 小胶质细胞内稳态AIM1结合了生物化学和遗传学工具来识别上游和下游 与CD22合作以抑制小胶质细胞中的吞噬作用的信号传导伴侣。目标2将阐明 以及在发育、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阻断后神经元对恢复小胶质细胞稳态的反应。最后，目标4将评估 阻断CD22改善AD小鼠模型认知功能下降的治疗潜力。这些 实验将揭示一种新的机制，小胶质细胞功能障碍，在正常老化与直接 翻译对AD患者的影响。

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.