Investigating the role of neuroinflammation on the accumulation and spread of tau pathology.

许多研究已经调查了炎症对淀粉样蛋白病理的影响，但其对tau病理严重程度的影响仍未得到充分研究。Tau是一种微管相关蛋白，在AD中过度磷酸化并在神经元中积累形成nft。与淀粉样斑块不同，AD患者NFT病理的严重程度与认知能力下降有关。在AD患者中，NFT的病理进展以一种典型的模式进行，首先影响内嗅皮层，其次是海马，最后扩散到新皮层。tau病理的渐进式积累和扩散已在动物模型中得到复制。我们已经证明，腹腔注射LPS或真实细菌（鼠伤寒沙门氏菌）诱导的全身性炎症通过激活内皮细胞和小胶质细胞加速正在进行的中枢神经系统疾病，最近的一项临床研究表明，暴露于全身性感染后，当血清促炎细胞因子水平升高时，认知功能下降速度加快5倍。这些研究表明，持续的低度全身性炎症是早期发病的主要危险因素。在这项合作研究中，我们的目标是验证全身性炎症加速tau病理的积累和传播从而促进疾病发病机制的假设。

Many studies have investigated the effect of inflammation on amyloid pathology, yet its effect on the severity of tau pathology remains understudied. Tau is a microtubule associated protein which in AD becomes hyperphosphorylated and accumulates in neurons to form NFTs. Unlike amyloid plaques, the severity of NFT pathology in AD correlates with cognitive decline. In AD patients, NFT pathology progresses in a stereotypical pattern affecting the entorhinal cortex first, followed by the hippocampus and finally spreading to the neocortex. The progressive accumulation and spread of tau pathology has been replicated in animal models. We have shown that systemic inflammation, induced by intraperitoneal injection of LPS or real life bacteria (Salmonella typhimurium) accelerates ongoing CNS disease via activation of endothelial cells and microglia and a recent clinical study showed 5-fold faster decline in cognitive function when serum levels of pro-inflammatory cytokines are elevated after exposure to a systemic infection. These studies suggest that sustained low grade systemic inflammation is a major risk factor for earlier onset of disease.In this collaborative study we aim to test the hypothesis that systemic inflammation accelerates the accumulation and spread of tau pathology thus contributing to disease pathogenesis.