T cells as modulators of microglial reactivity in Alzheimer’s disease

阿尔茨海默病（AD）是最常见的神经退行性疾病，病理定义为细胞外Aβ沉积、神经原纤维缠结和神经炎症。小胶质细胞是阿尔茨海默病病理生理的关键组成部分，可以调节疾病的进展。通过免疫疗法增强小胶质细胞对Aβ的清除目前正在阿尔茨海默病患者的临床试验中进行探索。与小胶质细胞介导的先天免疫反应相反，适应性免疫对阿尔茨海默病病理生理的贡献研究较少。然而，我们在初步实验中观察到，不同的适应性免疫细胞亚群侵入阿尔茨海默病的大脑；此外，我们在其他疾病模型中表明，脑入侵T细胞可以调节小胶质细胞表型。因此，本研究的目的是研究T细胞亚群对AD小胶质细胞表型的影响及其潜在的神经免疫学机制。我们将结合体外T细胞检测、体内细胞移植、遗传动物模型和转录组学来研究T细胞与小胶质细胞相互作用的详细机制。从两性动物模型中获得的关键发现将在从阿尔茨海默病患者身上获得的人脑样本中得到验证。该研究项目的结果将增加我们对小胶质细胞- t细胞串扰的机制理解，从而促进未来设计更安全和新颖的治疗AD的免疫治疗方法。

Alzheimer´s disease (AD) is the most prevalent neurodegenerative disorder and is pathologically defined by extracellular Aβ deposition, neurofibrillary tangles and neuroinflammation. Microglia are a key component in the pathophysiology of AD and can modulate the disease progression. Enhancing microglial clearance of Aβ by immunotherapy is currently explored in clinical trials with AD patients. In contrast to the microglia-mediated innate immune responses, the contribution of adaptive immunity to the pathophysiology of AD is less investigated. However, we have observed in our preliminary experiments that diverse adaptive immune cell subpopulations invade the AD brain; moreover, we showed in other disease models that brain-invading T cells can modulate the microglial phenotype. Therefore, the objective of this proposal is to investigate the impact of T cell subpopulations on microglial phenotypes and its underlying neuroimmunological mechanisms in AD. We will utilize a combination of ex vivo T cell assays, in vivo cell transplantation, genetic animal models and transcriptomics to study the detailed mechanisms of T cell-microglia interaction. Key findings from animal models in both sexes will then be validated in human brain samples obtained from AD patients. Results derived from this research project will increase our mechanistic understanding of microglia-T cell crosstalk and thereby facilitate the future design of more safe and novel immunotherapeutic approaches for the treatment of AD.