Promotion of Alzheimers Disease by Alcohol - Role of eCIRP

酒精促进阿尔茨海默病 - eCIRP 的作用

基本信息

批准号：
10264903
负责人：
PHILIPPE MARAMBAUD
金额：
$ 41.88万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-20 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10264903
关键词：
Affinity Alcohol consumption Alcohols Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Animal Model Animals Attenuated Binding Binding Proteins Blood - brain barrier anatomy Brain Calcium Calpain Cause of Death Cell membrane Cerebrospinal Fluid Development Dose Exposure to Fluorescence Resonance Energy Transfer Focused Ultrasound Future Gene Expression Goals IL6ST gene Impaired cognition Injections Interleukin 6 Receptor Interleukin Activation Intravenous JAK1 gene JAK2 gene Knockout Mice Link MAPT gene Mediating Mediator of activation protein Memory impairment Microglia Modeling Molecular Mus Nerve Degeneration Neurofibrillary Tangles Neurons Pathogenesis Pathologic Pathology Pathway interactions Patients Pattern Peptides Phosphotransferases Preventive RNA-Binding Proteins Role STAT3 gene Severities Signal Transduction Source Surface Plasmon Resonance TYK2 Tauopathies Therapeutic Therapeutic Effect Time Transgenic Organisms Up-Regulation Wild Type Mouse alcohol effect alcohol exposure alcohol measurement antibody inhibitor base binge drinking calpain inhibitor experimental study extracellular in vivo inhibitor/antagonist insight interleukin-6 receptor alpha neurodegenerative dementia neutralizing antibody novel protein expression public health relevance tau Proteins tau aggregation tau mutation tau phosphorylation

项目摘要

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.

项目描述：该R01提案的目的是通过在酒精时从小胶质细胞中释放出细胞外冷诱导的RNA结合蛋白（ECIRP）暴露，导致阿尔茨海默氏病（AD）的tau病理。广告是美国第六大死亡原因神经退行性痴呆的最常见形式。尽管研究将大量饮酒与 AD，尚未充分探索潜在的机制。我们已经证明ECIRP是关键暴露于暴饮暴食水平的酒精含量引起的记忆障碍介质，导致我们前往假设ECIRP可能是酒精与广告之间关系的关键参与者。确实，我们发现了 AD患者的脑脊液中的ECIRP增加。我们还表明酒精增加了在饮酒的动物模型中，ECIRP的大脑水平，而小胶质细胞是问题酒精暴露后，大脑中ECIRP的来源。此外，ECIRP增加了tau磷酸化和通过直接结合和激活白介素-6受体α上调CDK5高激活器p25 （IL-6Rα）/STAT3途径。根据这些新发现的结果，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途径，导致病理学tau磷酸 ation和聚合。我们还表明，CIRP衍生的肽C23有效抑制了激活 ECIRP诱导的IL-6Rα/STAT3/CDK5途径的IL-6Rα/CDK5途径。因此，我们进一步假设 C23减弱了酒精引起的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衍生的ECIRP在病理tau磷酸化和聚集中的作用。然后，我们将阐明ECIRP产生类似AD的病理TAU的分子机制磷酸化和聚集。最后，我们将检查抑制ECIRP是否会减弱tau 暴露于暴饮暴食水平的酒精水平后，磷酸化和聚集。这些研究将提供对负责大量饮酒影响的机制的新型关键见解 AD的发病机理以及将来治疗AD患者的新潜在理论策略。