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.

项目概要 该提案的长期目标是确定长期饮酒如何调节肝脏到大脑 轴诱导和/或促进阿尔茨海默病（AD）病理学研究主要集中在直接作用上。 酒精对大脑的作用以及从大脑外部观察酒精如何调节 AD 的研究 我们令人兴奋的初步数据已经确定了酒精引起的两种潜在变化。 肝脏可能会诱发和/或促进大脑中的 AD 病理。 进食会减少肝脏低密度脂蛋白受体-1 (LRP1)，这是一种清除外周血所必需的受体。 由于外周 Aβ 可以通过高级受体转运穿过血脑屏障 (BBB)。 糖化终末产物 (RAGE) 并沉积在大脑中，可以想象，改变了 LRP1 介导的 肝脏 Aβ 清除率可以显着影响脑 Aβ 负荷 其次，我们的工作表明周围型肿瘤。 酒精损伤时肝脏和其他器官分泌的坏死因子-α（TNF-α）会极大地影响 BBB 和 AD 病理学在 AD 转基因小鼠中，TNFR-Fc 融合蛋白阻断外周 TNF-α。 （依那西普）可减少 AD 病理，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 通透性增加而穿过脑内皮。 探索这些新的发现，以提供对酒精摄入如何改变肝脏的综合检查 该提案有两个具体目标：1) 描述其影响。 酒精对肝脏 Aβ 清除的影响，并检查其对外周到中枢 Aβ 稳态的影响。 工作假设是酒精摄入通过 LRP1 下调改变肝外周 Aβ 清除率 增加外周到中枢的 Aβ 负荷 2) 描述酒精性肝损伤引起的外周的影响。 炎症对神经血管和神经元变性及其对 AD 病理学的影响。 假设是酒精性肝损伤引起的外周炎症会导致 BBB 功能障碍，增加 AD 标志性病理学（Aβ 和 tau 缠结），并调节神经炎症，从而诱导和/或增强 AD 病理学。该提案将把肝脏/酒精研究领域的专家与 AD/BBB 领域的专家结合起来。 研究利用最先进的体内和体外技术对肝-脑轴进行全面探索 体外技术和模型，这将增加由此产生的新知识的协同作用和成功的可能性。 将能够识别新的治疗靶点并提供对酒精依赖的机制洞察 AD，并将描述肝脑轴在 AD 病理学中的重要性，这是一个尚未探索的概念 酒精依赖性 AD 的新兴领域。