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

项目总结 这项提议的长期目标是确定长期饮酒如何调节肝脏到大脑的比例。 AXIS诱导和/或促进阿尔茨海默病(AD)病理。研究主要集中在直接投资上。 酒精对大脑的作用以及了解酒精如何调节阿尔茨海默病的研究 缺乏病理学知识。我们令人兴奋的初步数据已经确定了酒精引起的两个潜在的变化 肝脏可以诱导和/或促进大脑中的AD病理。首先，我们发现慢性酒精 摄食减少肝脏低密度脂蛋白受体-1(LRP1)，这是去除外周血细胞所必需的受体 一辆β。由于外周A-β可以通过晚期受体转运通过血脑屏障。 糖基化终产物(RAGE)并沉积在大脑中，可以想象改变了LRP1介导的 肝Aβ清除量显著影响脑Aβ负荷。第二，我们的工作表明，周围肿瘤 酒精性损伤时肝脏和其他器官分泌的肿瘤坏死因子-α(肿瘤坏死因子-α)对 血脑屏障和AD病理。在AD转基因小鼠中，肿瘤坏死因子受体-Fc融合蛋白阻断外周血肿瘤坏死因子-α (依那西普)减少AD病理，我们令人兴奋的初步数据显示增强了Aβ(1-42)迁移 在体外由于肿瘤坏死因子-α介导的血脑屏障通透性增加而引起的跨脑内皮细胞。这项提议将 探索这些新的发现，以提供关于酒精摄入如何改变肝脏到肝脏的综合检查 脑轴诱导和/或促进AD病理。该提案有两个具体目标：1)勾勒出影响 酒精对肝脏清除Aβ的影响，并检测其对外周到中枢Aβ动态平衡的影响。我们的 工作假说是酒精摄入通过下调LRP1来改变肝脏外周Aβ清除 以增加外周到中枢的Aβ负载。2)酒精性肝损伤外周效应的表征 神经血管和神经元变性的炎症及其对AD病理的影响。我们的工作 假设酒精性肝损伤诱导的外周炎症导致血脑屏障功能障碍，增加AD 标志病理(Aβ和tau-angles)，并调节神经炎症，从而诱导和/或增强 公元病理学。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 研究利用体内和体内最先进的技术提供对肝脏到脑轴的全面探索 体外技术和模型，这将增加协同效应和成功的可能性。由此产生的新知识 将能够识别新的治疗靶点，并提供对酒精依赖的机械性洞察 AD，并将描绘肝到脑轴在AD病理中的重要性，这是一个在 酒精依赖型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.