Promotion of Alzheimers Disease by Alcohol - Role of eCIRP

项目描述：该R01提案的目标是通过以下方式研究一种新的分子机制 酒精作用下小胶质细胞释放的细胞外冷诱导RNA结合蛋白(ECIRP) 暴露，导致阿尔茨海默病(AD)的tau病理。AD是美国第六大死因 也是最常见的神经退行性痴呆。尽管研究将大量饮酒与 然而，其潜在的机制尚未得到充分的探讨。我们已经证明了eCIRP是一个关键的 暴露在酗酒水平下导致记忆障碍的中介，导致我们 推测eCIRP可能在酒精与AD的关系中起关键作用。事实上，我们发现 AD患者脑脊液中eCIRP升高。我们还表明，酒精会增加人的 酗酒动物模型中脑内eCIRP的水平，小胶质细胞可能是 酒精暴露后脑内eCIRP的来源。此外，eCIRP还增加了tau的磷酸化和 通过与白细胞介素6受体α的直接结合和激活上调cdk5超激活因子p25 (IL-6Rα)/STAT3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-6Rα/STAT3/CDK5通路，导致病理性tau磷酸化。 聚合和聚合。我们还发现CIRP衍生的多肽C23有效地抑制了这种激活。 ECIRP诱导的IL-6Rα/STAT3/CDK5通路。因此，我们进一步假设，治疗与 C23抑制酒精诱导的tau病理的发展。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来源的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tau的分子机制 磷酸化和聚集。最后，我们将研究用C23抑制eCIRP是否减弱tau。 过量饮酒后的磷酸化和聚集。这些研究将提供 对酗酒对健康的影响机制的新的关键见解 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.