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.