Immunomodulatory and behavioral effects of CAR T regulatory cell 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，沿着胶质介导的神经炎症和异常蛋白聚集体的形成 纤维是AD的标志AD的散发性和家族性形式具有过度产生和/或减少的 细胞外淀粉样β（Aβ）肽的清除和扭曲的tau蛋白纤维的神经元内缠结。 已知神经炎症发生在AD中，当与Aβ斑块附近相关时， 神经变性此外，外周免疫活性和炎症可以影响炎症， CNS。调节性T细胞（TcR）是具有固有抗炎和免疫调节功能的T细胞亚群。 免疫调节特性。在稳态条件下，在CNS中发现了睾酮， 中枢神经系统炎症区域。在AD患者中发现TdR活性降低或数量减少， TdR的耗尽可加速鼠AD模型中的认知缺陷。我们假设表达T细胞的 对淀粉样蛋白β（Aβ）具有特异性的嵌合抗原受体（汽车）将具有免疫调节活性， 改善5xFAD B6小鼠（一种鼠AD模型）的认知功能。本提案的目的是测试 将展示经工程化以表达针对淀粉样蛋白β的汽车的TcR的创新概念 在CNS和外周组织中的免疫调节作用，导致认知行为改善。的 产生的数据将提供关键的概念验证数据，以向前发展这种新的治疗思想。

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.