Modulation of the liver-brain axis by alcohol and its impact on Alzheimers disease pathology

酒精对肝脑轴的调节及其对阿尔茨海默病病理学的影响

• 批准号: 10543357
• 负责人: DERICK S HAN
• 金额: $ 2.59万
• 依托单位: KECK GRADUATE INST OF APPLIED LIFE SCIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543357
• 关键词: AD transgenic mice; Abeta clearance; Affect; Alcohol consumption; Alcohol dependence; Alcohol-Induced Disorders; Alcoholic Liver Diseases; Alcohols; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; American; Amyloid beta-Protein; Area; Biological Products; Blood - brain barrier anatomy; Brain; Cause of Death; Chimeric Proteins; Chronic; Data; Deposition; Development; Dichloromethylene Diphosphonate; Down-Regulation; Endothelium; Etanercept; Fc Receptor; Functional disorder; Goals; Hepatic; Homeostasis; In Vitro; Inflammation; Knowledge; Kupffer Cells; Lipoprotein Receptor; Liposomes; Liver; Low Density Lipoprotein Receptor; Mediating; Metabolic; Modeling; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neuronal Injury; Organ; Pathology; Peripheral; Plasma Proteins; Research; Role; Source; Specialist; TNF gene; TNFRSF1A gene; Techniques; Testing; United States; Work; alcohol effect; alcohol research; blood-brain barrier disruption; blood-brain barrier permeabilization; brain health; chronic alcohol ingestion; feeding; in vivo; insight; knowledge of results; liver function; liver injury; migration; monolayer; neuroinflammation; neurovascular; new therapeutic target; novel; overexpression; problem drinker; receptor; receptor for advanced glycation endproducts; success; synergism; tau Proteins; wasting

PROJECT SUMMARY The long-term goal of this proposal is to determine how chronic alcohol intake modulates the liver-to-brain axis to induce and/or promote Alzheimer’s disease (AD) pathology. Studies have largely focused on the direct action of alcohol on the brain and studies looking outside the brain to understand how alcohol modulates AD pathology are lacking. Our exciting preliminary data have identified two potential alcohol-induced changes to the liver that could induce and/or promote AD pathology in the brain. First, we have discovered that chronic alcohol feeding reduces hepatic low-density lipoprotein receptor-1 (LRP1), a receptor essential in removing peripheral Aβ. Since peripheral Aβ can be transported across the blood-brain barrier (BBB) by receptor for advanced glycation end products (RAGE) and become deposited in the brain, it is conceivable that altered LRP1-mediated hepatic Aβ clearance can significantly affect brain Aβ load. Second, our work shows that peripheral tumor necrosis factor-α (TNF-α) secreted by the liver and other organs during alcohol-induced injury can greatly impact the BBB and AD pathology. In AD transgenic mice, peripheral TNF-α blockage by the TNFR-Fc fusion protein (etanercept) reduces AD pathology, and our exciting preliminary data shows enhanced Aβ(1-42) migration across the brain endothelium due to TNF-α-mediated increase in BBB-permeability in vitro. This proposal will explore these novel findings to provide an integrated examination of how alcohol intake may alter the liver-to- brain axis to induce and/or promote AD pathology. The proposal has two specific aims: 1) Delineate the effect of alcohol on Aβ clearance by the liver and examine its impact on peripheral-to-central Aβ homeostasis. Our working hypothesis is that alcohol intake alters hepatic peripheral Aβ clearance through LRP1 downregulation to increase peripheral-to-central Aβ load. 2) Characterize the effect of alcoholic-liver-injury-induced peripheral inflammation on neurovascular- and neuronal-degeneration, and its impact on AD pathology. Our working hypothesis is that alcoholic-liver-injury-induced peripheral inflammation causes BBB dysfunction, increases AD hallmark pathology (Aβ and tau-tangles), and modulates neuroinflammation, thereby inducing and/or potentiating AD pathology. The proposal will combine specialists in the areas of liver/alcohol research with those in AD/BBB research to provide a comprehensive exploration of the liver-to-brain axis utilizing state-of-the-art in vivo and in vitro techniques and models, which will increase synergy and likelihood of success. The resulting new knowledge will enable the identification of new therapeutic-targets and provide mechanistic insight into alcohol-dependent AD, and will delineate the importance of the liver-to-brain axis in AD pathology, an unexplored concept in the emerging field of alcohol-dependent AD.

项目摘要 该提议的长期目标是确定慢性酒精摄入量如何调节肝脏至脑 轴诱导和/或促进阿尔茨海默氏病（AD）病理学。研究主要集中于直接 酒精对大脑的作用，并研究在大脑外看，以了解酒精如何调节AD 缺乏病理。我们令人兴奋的初步数据已经确定了两种潜在的酒精引起的变化 可能影响和/或促进大脑中AD病理的肝脏。首先，我们发现慢性酒精 进食可减少肝低密度脂蛋白受体-1（LRP1），这是去除周围必不可少的受体 Aβ。由于外围Aβ可以通过受体在血脑屏障（BBB）上运输 糖化末端产物（愤怒）并沉积在大脑中，可以想象是改变了LRP1介导的 肝Aβ清除率可以显着影响大脑Aβ负载。其次，我们的工作表明外围肿瘤 在酒精引起的损伤期间由肝脏和其他器官分泌的坏死因子-α（TNF-α）可能是很大的影响 BBB和AD病理学。在AD转基因小鼠中，TNFR-FC融合蛋白的周围TNF-α阻塞 （Etanercept）减少了AD病理学，我们令人兴奋的初步数据显示Aβ（1-42）迁移增强 由于TNF-α介导的体外BBB渗透性增加，整个脑内皮介导。该提议将 探索这些新颖的发现，以提供对酒精摄入如何改变肝脏至上的综合检查 脑轴诱导和/或促进AD病理。该提案有两个具体的目的：1）描述效果 肝脏对Aβ清除的酒精对外围至中心Aβ稳态的影响。我们的 工作假设是，酒精摄入量通过LRP1下调改变了肝外围Aβ清除率 增加外围至中心Aβ负载。 2）表征酒精 - 炎症诱导的外围的效果 神经血管和神经元脱生的炎症及其对AD病理的影响。我们的工作 假设是酒精肝受伤引起的周围感染会引起BBB功能障碍，增加了AD 标志性病理（Aβ和tau tangles），并调节神经炎症，从而诱导和/或增强 广告病理学。该提案将在肝脏/酒精研究领域与AD/BBB中的专家相结合 研究利用体内最先进的肝脏到脑轴的全面探索 体外技术和模型，这将增加成功的协同作用和可能性。由此产生的新知识 将能够识别新的治疗靶标，并为酒精依赖性提供机械洞察力 AD，并将描述肝脏到脑轴在AD病理学中的重要性，这是一个意外的概念 依赖酒精的AD的新兴领域。