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

阿尔茨海默病（Alzheimer's disease，AD）是最常见的神经退行性疾病，其病理特征为细胞外Aβ沉积、神经元缠结和神经炎症。小胶质细胞是AD病理生理学的关键组成部分，可以调节疾病的进展。目前在AD患者的临床试验中探索了通过免疫疗法增强小胶质细胞对Aβ的清除。与小胶质细胞介导的先天性免疫反应相比，获得性免疫对AD病理生理学的贡献研究较少。然而，在我们的初步实验中，我们观察到不同的适应性免疫细胞亚群侵入AD大脑;此外，我们在其他疾病模型中表明，侵入大脑的T细胞可以调节小胶质细胞表型。因此，本研究的目的是探讨AD患者T细胞亚群对小胶质细胞表型的影响及其潜在的神经免疫学机制。我们将利用体外T细胞检测、体内细胞移植、遗传动物模型和转录组学的组合来研究T细胞-小胶质细胞相互作用的详细机制。然后，将在从AD患者获得的人脑样本中验证来自两种性别动物模型的关键发现。来自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.