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 提案的目标是通过以下方式研究一种新颖的分子机制：酒精作用下小胶质细胞释放细胞外冷诱导 RNA 结合蛋白 (eCIRP) 暴露，导致阿尔茨海默氏病 (AD) 的 tau 蛋白病理，AD 是美国第六大死因。尽管研究将大量饮酒与神经退行性痴呆症联系起来。 AD，其基本机制尚未得到充分探索，我们已经证明 eCIRP 是一个关键因素。酗酒引起的记忆障碍的介导因素，导致我们假设 eCIRP 可能是酒精与 AD 之间关系的关键因素。事实上，我们发现。 AD 患者脑脊液中的 eCIRP 增加，我们还发现酒精增加了 eCIRP。酗酒动物模型中 eCIRP 的大脑水平，并且小胶质细胞可能是酒精暴露后大脑中 eCIRP 的来源此外，eCIRP 增加了 tau 磷酸化和通过直接结合并激活白细胞介素 6 受体 α，上调 Cdk5 过度激活因子 p25 (IL-6Rα)/STAT3 通路基于这些新发现，我们捕获了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 磷酸化我们还表明 CIRP 衍生肽 C23 有效抑制了激活。因此，我们进一步采用了 eCIRP 诱导的 IL-6Rα/STAT3/Cdk5 通路。 C23 减弱酒精引起的 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样病理性tau蛋白的分子机制最后，我们将检查 C23 抑制 eCIRP 是否会减弱 tau 蛋白。这些研究将提供暴露于酗酒水平后的磷酸化和聚集。对酗酒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。