Chimeric antigen receptor T regulatory cells as therapy for Alzheimer's Disease

项目概要/摘要： 阿尔茨海默病（AD）是一种进行性神经退行性疾病，其是阿尔茨海默病的主要原因之一。 60岁后的记忆障碍和痴呆症。额叶皮层神经元功能障碍和死亡 和海马，沿着小胶质细胞介导的神经炎症和异常蛋白的形成 聚集体和原纤维是AD的标志。散发性和家族性AD具有过度生产和/或 减少细胞外淀粉样β（Aβ）肽的清除和扭曲tau蛋白的神经元内缠结 纤维已知神经炎症发生在AD中，当与Aβ斑块附近相关时， 神经变性数据表明，炎症性小胶质细胞，中枢神经系统的常驻巨噬细胞， 系统，在神经变性和认知能力下降中起作用。调节性T细胞（Tlymphocyte，Tlymphocyte）是T细胞的一个亚群 具有固有的抗炎和免疫调节特性。在中枢神经系统中， 稳态条件和增加向CNS炎症区域的运输。活动减少或减少 已经在AD患者中发现了大量的TdR，TdR的消耗可以加速AD患者的认知缺陷。 鼠AD模型。我们假设表达嵌合抗原受体（汽车）的TcR对 β淀粉样蛋白（Aβ）在脑内具有治疗性免疫调节和局部疾病修饰活性， Aβ积聚和进行性神经变性的区域。该提案的目的是测试创新的 这一概念是，经工程化以表达针对Aβ的汽车的TcR将表现出免疫调节性， 阿尔茨海默病小鼠模型的神经保护活性。我们将测试鼠和人的T细胞， 当Aβ存在时，AD模型中的活性。生成的数据将提供关键的概念验证数据， 这种新的治疗理念

Project Summary/Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disease that is one of the primary reasons for memory dysfunction and dementia after 60 years of age. Neuronal dysfunction and death in the frontal cortex and hippocampus, along with microglia-mediated neuroinflammation and formation of aberrant protein aggregates and fibrils are hallmarks of AD. Sporadic and familial forms of AD have an overproduction and/or decreased clearance of extracellular amyloid-beta (Aβ) peptides and intraneuronal tangles of twisted tau protein fibers. Neuroinflammation is known to occur in AD, and when associated near Aβ plaques there is a greater neurodegeneration. Data suggest that inflammatory microglia, the resident macrophages of the central nervous system, have a role in neurodegeneration and cognitive decline. T regulatory cells (Tregs) are a subset of T cells that have inherent anti-inflammatory and immunomodulatory properties. Tregs are found in the CNS under steady state conditions and increase trafficking to regions of CNS inflammation. Less active or decreased numbers of Tregs has been found in AD patients and depletion of Tregs can accelerate cognitive defects in murine AD models. We hypothesize that Tregs expressing chimeric antigen receptors (CARs) with specificity to amyloid-beta (Aβ) would have therapeutic immunomodulatory and localized disease-modifying activity at brain regions of Aβ accumulation and progressive neurodegeneration. The aim of this proposal is to test the innovative concept that Tregs engineered to express CARs against Aβ will demonstrate immunoregulatory and neuroprotective activities in mouse models of Alzheimer's disease. We will test murine and human Tregs for activity in AD models when Aβ is present. The data generated will provide key proof-of-concept data to move this novel therapeutic idea forward