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学的影响，但其对tau病理学严重程度的影响仍然研究不足。Tau是微管相关蛋白，其在AD中变得过度磷酸化并在神经元中积累以形成NFT。与淀粉样斑块不同，AD中NFT病理的严重程度与认知能力下降相关。在AD患者中，NFT病理学以刻板模式进展，首先影响内嗅皮层，其次是海马，最后扩散到新皮层。tau病理学的进行性积累和扩散已在动物模型中复制。我们已经表明，由腹腔内注射LPS或真实的细菌（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进行中的CNS疾病，并且最近的临床研究表明，当暴露于全身性感染后促炎细胞因子的血清水平升高时，认知功能下降快5倍。这些研究表明，持续的低度全身性炎症是疾病早期发作的主要危险因素。在这项合作研究中，我们的目的是验证系统性炎症加速tau病理的积累和传播从而有助于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.