Promotion of Alzheimers Disease by Alcohol - Role of eCIRP

项目描述：本R 01提案的目标是通过以下方法研究一种新的分子机制： 这种细胞外冷诱导RNA结合蛋白（eCIRP），在酒精作用下从小胶质细胞中释放出来， 暴露，导致阿尔茨海默病（AD）中的tau病理学。AD是美国第六大死亡原因 也是最常见的神经退行性痴呆尽管研究表明酗酒与 AD的潜在机制尚未得到充分探讨。我们已经证明，eCIRP是一个关键的 介质的记忆损伤诱导暴露于酗酒水平的酒精，导致我们， 假设eCIRP可能是酒精和AD之间关系的关键参与者。我们发现， AD患者脑脊液中eCIRP升高。我们还发现酒精增加了 大脑中的eCIRP水平在酗酒的动物模型，小胶质细胞是可能的 酒精暴露后大脑中eCIRP的来源。此外，eCIRP增加tau蛋白磷酸化， 通过直接结合和激活白细胞介素-6受体α上调Cdk 5超活化因子p25 （IL-6 R α）/STAT 3通路。基于这些新的发现，我们假设酒精诱导的小胶质细胞- 衍生的eCIRP激活神经元IL-6 R α/STAT 3/Cdk 5通路，导致病理性tau磷酸化， 化和聚集。我们还表明，CIRP衍生的肽C23有效地抑制了活化， eCIRP诱导的IL-6 R α/STAT 3/Cdk 5通路。因此，我们进一步假设， C23减弱酒精诱导的tau病理学的发展。在这个项目中，我们计划进一步建立 酒精诱导的小胶质细胞衍生的eCIRP在病理性tau磷酸化和聚集中的作用。 然后，我们将阐明eCIRP产生AD样病理性tau蛋白的分子机制 磷酸化和聚集。最后，我们将检查用C23抑制eCIRP是否减弱tau蛋白， 磷酸化和聚集后暴露于酗酒水平的酒精。这些研究将提供 新的关键见解的机制负责的影响，大量饮酒对 AD的发病机制，以及未来治疗AD患者的新的潜在治疗策略。

PROJECT DESCRIPTION: The goal of this R01 proposal is to investigate a novel molecular mechanism by which extracellular cold-inducible RNA-binding protein (eCIRP), released from microglial cells upon alcohol exposure, leads to tau pathology in Alzheimer’s disease (AD). AD is the 6th leading cause of death in the US and the most common form of neurodegenerative dementia. Although studies link heavy alcohol drinking to AD, the underlying mechanisms have not been sufficiently explored. We have shown that eCIRP is a critical mediator of memory impairment induced by exposure to binge-drinking levels of alcohol, leading us to postulate that eCIRP may be a key player in the relationship between alcohol and AD. Indeed, we discovered that eCIRP was increased in the cerebrospinal fluid of AD patients. We also showed that alcohol increased the brain levels of eCIRP in an animal model of binge alcohol drinking, and that microglial cells are the probable source of eCIRP in the brain after alcohol exposure. Moreover, eCIRP increased tau phosphorylation and upregulated the Cdk5 hyperactivator p25 via the direct binding to and activation of the interleukin-6 receptor α (IL-6Rα)/STAT3 pathway. Based on these novel findings, we hypothesize that alcohol-induced microglial cell- derived eCIRP activates the neuronal IL-6Rα/STAT3/Cdk5 pathway, leading to pathological tau phosphoryl- ation and aggregation. We also showed that the CIRP-derived peptide C23 effectively inhibited the activation of the IL-6Rα/STAT3/Cdk5 pathway induced by eCIRP. Therefore, we further hypothesize that treatment with C23 attenuates the development of alcohol-induced tau pathology. In this project, we plan to further establish the role of alcohol-induced microglial cell-derived eCIRP in pathological tau phosphorylation and aggregation. We will then elucidate the molecular mechanism through which eCIRP produces AD-like pathological tau phosphorylation and aggregation. Finally, we will examine whether inhibition of eCIRP with C23 attenuates tau phosphorylation and aggregation after exposures to binge-drinking levels of alcohol. These studies will provide novel pivotal insights into the mechanisms responsible for the influence of heavy alcohol drinking on the pathogenesis of AD, as well as a new potential therapeutic strategy to treat AD patients in the future.