Gardner L E, White J D, Eimerbrink M J, Boehm G W, Chumley M J
Department of Biology, Neurobiology of Aging Collaborative, Texas Christian University, Fort Worth, TX 76129, USA.
Department of Psychology, Neurobiology of Aging Collaborative, Texas Christian University, Fort Worth, TX 76129, USA.
Neuroscience. 2016 Sep 7;331:72-7. doi: 10.1016/j.neuroscience.2016.06.007. Epub 2016 Jun 16.
For years, the prevailing hypothesis for Alzheimer's Disease (AD) has proposed a mechanism by which deposition of amyloid-beta (Aβ) in the brain is independent of tau-pathologies and cognitive decline. However, despite extensive research on the disease, the mechanisms underlying the etiology of tau-pathology remain unknown. Previous research in our lab has shown that imatinib methanesulfonate (IM) blocks the peripheral production of Aβ in response to LPS, thereby preventing the buildup of Aβ in the hippocampus, and rescuing the cognitive dysfunction that normally follows. The present study aimed to examine the link between Aβ and tau following inflammation, and to expand our understanding of how IM affects AD pathology. Specifically, we hypothesized that the IM-mediated inhibition of Aβ production following inflammation would successfully protect against the hyperphosphorylation of tau (ptau). Here we show that 7days of LPS treatment in male C57BL/6J mice, which normally produces elevations in peripheral and central Aβ, also produces hyperphosphorylation of tau. However, just as pre-treatment and concurrent treatment with IM blocks Aβ production, it also blocks the phosphorylation of tau. In addition, 7days of LPS-induced inflammation and Aβ production also leads to elevated total tau protein expression. Our results may provide support for the hypothesis that enhanced expression of tau following LPS administration is a protective measure by hippocampal neurons to compensate for the loss of the microtubule-stabilizing protein due to phosphorylation. More importantly, our results support the hypothesis that blocking the production of Aβ that follows inflammation also leads to reduced tau phosphorylation, lending credence to a model in which Aβ initiates tau phosphorylation.
多年来，关于阿尔茨海默病（AD）的主流假说提出了一种机制，即大脑中β淀粉样蛋白（Aβ）的沉积独立于tau病理和认知衰退。然而，尽管对该疾病进行了广泛研究，但tau病理病因背后的机制仍然未知。我们实验室之前的研究表明，甲磺酸伊马替尼（IM）可阻止外周对脂多糖（LPS）产生Aβ，从而防止海马体中Aβ的积累，并挽救随之而来的认知功能障碍。本研究旨在探讨炎症后Aβ与tau之间的联系，并扩展我们对IM如何影响AD病理的理解。具体而言，我们假设炎症后IM介导的Aβ产生抑制将成功预防tau的过度磷酸化（ptau）。在这里我们表明，在雄性C57BL/6J小鼠中进行7天的LPS治疗，通常会导致外周和中枢Aβ升高，同时也会导致tau的过度磷酸化。然而，正如IM预处理和同时治疗可阻止Aβ产生一样，它也能阻止tau的磷酸化。此外，7天的LPS诱导炎症和Aβ产生还会导致总tau蛋白表达升高。我们的结果可能支持以下假说：LPS给药后tau表达增强是海马神经元的一种保护措施，以补偿由于磷酸化导致的微管稳定蛋白的损失。更重要的是，我们的结果支持以下假说：阻断炎症后Aβ的产生也会导致tau磷酸化减少，这为Aβ启动tau磷酸化的模型提供了可信度。
