Immunomodulatory and behavioral effects of CAR T regulatory cell therapy for Alzheimer's Disease”.

项目摘要/摘要： 阿尔茨海默病(AD)是一种进行性神经退行性疾病，是导致 60岁后记忆障碍和痴呆。额叶皮质中的神经元功能障碍和死亡 和海马区，以及胶质细胞介导的神经炎症和异常蛋白聚集体的形成 纤维是阿尔茨海默病的特征。散发性和家族性阿尔茨海默病生产过剩和/或减少 细胞外淀粉样β蛋白(Aβ)多肽和缠绕的tau蛋白纤维的神经元内缠结的清除。 已知在AD中会发生神经炎症，当与Aβ斑块附近相关时， 神经退行性变。此外，外周免疫活动和炎症可以影响炎症反应。 中枢神经系统。T调节细胞(Tregs)是T细胞的一个亚群，具有内在的抗炎和 免疫调节特性。树在中枢神经系统中被发现处于稳定状态，并增加了人口贩运 中枢神经系统炎症区域。在AD患者中发现Tregs活性降低或数量减少 Tregs的耗尽会加速小鼠AD模型中的认知缺陷。我们假设特雷格斯表达了 具有淀粉样β蛋白(Aβ)特异性的嵌合抗原受体(CARS)将具有免疫调节活性和 改善5xFAD B6小鼠的认知功能。这项提议的目的是测试 Tregs设计的用于表达汽车对抗淀粉样β蛋白的创新概念将展示 中枢神经系统和外周组织中的免疫调节作用导致认知行为的改善。这个 产生的数据将提供关键的概念验证数据，以发展这一新的治疗想法。

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 glia-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. Furthermore, peripheral immune activity and inflammation can affect inflammation in the CNS. 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) will have immunomodulatory activity and improve cognitive function of the 5xFAD B6 mice, a murine AD model. The aim of this proposal is to test the innovative concept that Tregs engineered to express CARs against amyloid-beta will demonstrate immunomodulatory effects in the CNS and in the peripheral tissues resulting in improved cognitive behavior. The data generated will provide key proof-of-concept data to develop this novel therapeutic idea forward.