The role of STAT1 signal transduction in the pathogenesis of Alzheimer's disease

越来越多的证据表明，神经炎症有助于阿尔茨海默病（AD）的进展和严重程度，而不仅仅是由新出现的淀粉样蛋白-β斑块和神经原纤维缠结引发的旁观者效应。组织学上，活化的小胶质细胞聚集在β-淀粉样蛋白沉积物周围，表明这些细胞的吞噬作用对淀粉样蛋白斑块的形成或清除很重要。信号转导和转录激活因子（STAT）蛋白作为免疫反应的关键转录因子，在AD的病理生理过程中发挥着重要作用。在我们两个合作小组的初步数据中，我们发现与AD相关斑块沉积相关的慢性神经炎症导致炎性细胞因子表达增加，进而激活STAT 1。使用转基因AD样小鼠模型（5XFAD），我们发现STAT 1表达的缺失导致Iba 1阳性小胶质细胞数量显著减少，这与小鼠不同脑区Aβ斑块负荷显著降低相关。项目提案中概述的进一步实验将需要评估STAT 1信号传导中不同故障对β-淀粉样前体蛋白（APP）加工，斑块形成调节和记忆障碍发展的功能影响。研究翻译后修饰的作用，特别是STAT 1在分子、细胞和器官水平上的序列特异性、协同DNA结合，将进一步深入了解导致AD认知缺陷的基本病理机制。

Increasing evidence suggests that neuroinflammation contributes to the progression and severity of Alzheimer´s disease (AD), rather than being a mere bystander effect triggered by emerging amyloid-β plaques and neurofibrillar tangles. Histopathologically, activated microglia cluster around β-amyloid deposits, suggesting that phagocytosis by these cells is important for either the formation or clearance amyloid plaques. STAT (signal transducer and activator of transcription) proteins which function as key transcription factors in orchestrating immune reactions may play a crucial role in the pathophysiology of AD. In preliminary data from our two collaborating groups, we showed that chronic neuroinflammation associated with AD-related plaque deposition resulted in an increased expression of inflammatory cytokines, which in turn activated STAT1. Using a transgenic AD-like mouse model (5XFAD), we found that the absence of STAT1 expression resulted in a significantly reduced number of Iba1-positive microglial cells which was associated with a dramatically lower Aβ plaque load in various murine brain regions. Further experiments outlined in the project proposal will be required to assess the functional impact of different malfunctions in STAT1 signaling on the processing of β-amyloid precursor protein (APP), the regulation of plaque formation and the development of memory impairment. Studying the role of post-translation modifications and, in particular, sequence-specific, cooperative DNA binding of STAT1 at the molecular, cellular and organismic level, will provide further insight into the essential pathomechanisms leading to cognitive deficits in AD.