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

项目摘要 这项提案的长期目标是确定慢性酒精摄入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。研究主要集中在直接 酒精对大脑的作用以及研究大脑外部以了解酒精如何调节AD 病理学缺乏。我们令人兴奋的初步数据已经确定了两个潜在的酒精诱导的变化， 肝脏，可能诱导和/或促进脑中的AD病理。首先，我们发现长期酗酒 进食减少肝脏低密度脂蛋白受体-1（LRP 1），这是一种在去除外周血中必不可少的受体。 Aβ。由于外周血Aβ可通过晚期脑缺血受体转运穿过血脑屏障， 糖基化终产物（glycation end products，LRP 1）的改变并沉积在脑中，可以想象，改变的LRP 1介导的糖基化终产物（glycation end products，LRP 1）可能是一种重要的糖基化终产物。 肝脏Aβ清除率可显著影响脑内Aβ负荷。其次，我们的工作表明，外周性肿瘤 在酒精诱导的损伤过程中，肝脏和其他器官分泌的坏死因子-α（TNF-α）可以极大地影响 BBB和AD病理学。在AD转基因小鼠中，TNFR-Fc融合蛋白对外周TNF-α的阻断 （依那西普）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渗透性增加而穿过脑内皮。这项建议会 探索这些新的发现，以提供一个综合检查酒精摄入如何可能改变肝脏， 脑轴诱导和/或促进AD病理。该提案有两个具体目标：1）描绘效果 酒精对肝脏Aβ清除率的影响，并检查其对外周-中枢Aβ稳态的影响。我们 工作假设是酒精摄入通过LRP 1下调改变肝脏外周Aβ清除率 增加外周-中枢Aβ负荷。2)描述酒精性肝损伤诱导的外周 炎症对神经血管和神经元变性的影响及其对AD病理学的影响。我们的工作 假设酒精性肝损伤诱导的外周炎症导致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领域的专家联合收割机 研究利用最先进的体内和体内技术， 体外技术和模型，这将增加协同作用和成功的可能性。由此产生的新知识 将能够识别新的治疗靶点，并为酒精依赖性 并将描绘AD病理学中肝脑轴的重要性，这是一个未探索的概念， 酒精依赖性AD的新兴领域。

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.