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。 β淀粉样蛋白（Aβ）。由于外周Aβ可通过受体转运穿过血脑屏障， 晚期糖基化终末产物（AGEs）并沉积在大脑中，可以想象，改变的LRP 1- 介导的肝脏Aβ清除可显著影响脑Aβ负荷。其次，我们的工作表明， 在酒精诱导的损伤过程中，肝脏和其他器官分泌的肿瘤坏死因子-α（TNF-α）可大大 影响BBB和AD病理学。在AD转基因小鼠中，TNFR-Fc融合物对外周TNF-α的阻断作用 蛋白质（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）增强 由于TNF-α介导的体外BBB渗透性增加而穿过脑内皮的迁移。这 一项提案将探讨这些新的发现，以提供一个综合的检查，酒精摄入量如何可能改变 肝-脑轴诱导和/或促进AD病理。该提案有两个具体目标：1）界定 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。 我们的工作假设是酒精摄入通过LRP 1改变肝脏外周Aβ清除率 下调以增加外周至中枢Aβ负荷。2)描述酒精性肝损伤的影响 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病理的影响。 我们的工作假设是酒精性肝损伤诱导的外周炎症导致血脑屏障功能障碍， 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。该提案将联合收割机在肝脏/酒精研究领域的专家 与那些在AD/BBB研究提供了一个全面的探索肝脑轴利用状态- 最先进的体内和体外技术和模型，这将增加协同作用和成功的可能性。的 由此产生的新知识将能够识别新的治疗靶点， 酒精依赖性AD，并将描绘AD病理学中肝脑轴的重要性， 这是酒精依赖性AD这一新兴领域中一个尚未探索的概念。

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 amyloid-beta (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.