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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：
10689797
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/10689797
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 Brain Calcium Calpain Cause of Death Cell membrane Cerebrospinal Fluid Cytoplasm 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 Memory impairment Microglia Modeling Molecular Mus Nerve Degeneration Neurofibrillary Tangles Neurons Pathogenesis Pathologic Pathology Pathway interactions Pattern Peptides Phosphorylation Phosphotransferases Preventive Probability 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 binge drinking blood-brain barrier crossing calpain inhibitor experimental study extracellular hyperphosphorylated tau in vivo inhibitor insight interleukin-6 receptor alpha neurodegenerative dementia neutralizing antibody novel protein expression public health relevance tau Proteins tau aggregation tau mutation tau-1

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：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， 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。