Garcia Jerome, Chang Rudy, Steinberg Ross A, Arce Aldo, Yang Joshua, Van Der Eb Peter, Abdullah Tamara, Chandrashekar Devaraj V, Eck Sydney M, Meza Pablo, Liu Zhang-Xu, Cadenas Enrique, Cribbs David H, Kaplowitz Neil, Sumbria Rachita K, Han Derick
Department of Biology, University of La Verne, Verne, CA, United States.
Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, United States.
Front Physiol. 2022 Sep 15;13:930402. doi: 10.3389/fphys.2022.930402. eCollection 2022.
Heavy alcohol consumption is a known risk factor for various forms of dementia and the development of Alzheimer's disease (AD). In this work, we investigated how intragastric alcohol feeding may alter the liver-to-brain axis to induce and/or promote AD pathology. Four weeks of intragastric alcohol feeding to mice, which causes significant fatty liver (steatosis) and liver injury, caused no changes in AD pathology markers in the brain [amyloid precursor protein (APP), presenilin], except for a decrease in microglial cell number in the cortex of the brain. Interestingly, the decline in microglial numbers correlated with serum alanine transaminase (ALT) levels, suggesting a potential link between liver injury and microglial loss in the brain. Intragastric alcohol feeding significantly affected two hepatic proteins important in amyloid-beta (Aβ) processing by the liver: 1) alcohol feeding downregulated lipoprotein receptor-related protein 1 (LRP1, ∼46%), the major receptor in the liver that removes Aβ from blood and peripheral organs, and 2) alcohol significantly upregulated APP (∼2-fold), a potentially important source of Aβ in the periphery and brain. The decrease in hepatic LRP1 and increase in hepatic APP likely switches the liver from being a remover or low producer of Aβ to an important source of Aβ in the periphery, which can impact the brain. The downregulation of LRP1 and upregulation of APP in the liver was observed in the first week of intragastric alcohol feeding, and also occurred in other alcohol feeding models (NIAAA binge alcohol model and intragastric alcohol feeding to rats). Modulation of hepatic LRP1 and APP does not seem alcohol-specific, as ob/ob mice with significant steatosis also had declines in LRP1 and increases in APP expression in the liver. These findings suggest that liver steatosis rather than alcohol-induced liver injury is likely responsible for regulation of hepatic LRP1 and APP. Both obesity and alcohol intake have been linked to AD and our data suggests that liver steatosis associated with these two conditions modulates hepatic LRP1 and APP to disrupt Aβ processing by the liver to promote AD.
大量饮酒是导致各种形式痴呆症和阿尔茨海默病（AD）发生的已知风险因素。在这项研究中，我们研究了灌胃给予酒精如何改变肝脑轴，从而诱导和/或促进AD病理变化。对小鼠进行四周的灌胃酒精喂养，这会导致显著的脂肪肝（脂肪变性）和肝损伤，但除了大脑皮质中小胶质细胞数量减少外，大脑中AD病理标志物[淀粉样前体蛋白（APP）、早老素]没有变化。有趣的是，小胶质细胞数量的减少与血清丙氨酸转氨酶（ALT）水平相关，这表明肝损伤与大脑中小胶质细胞的丢失之间可能存在联系。灌胃给予酒精显著影响肝脏中对β淀粉样蛋白（Aβ）加工重要的两种肝蛋白：1）酒精喂养下调了脂蛋白受体相关蛋白1（LRP1，约46%），它是肝脏中从血液和外周器官清除Aβ的主要受体；2）酒精显著上调了APP（约2倍），APP在外周和大脑中可能是Aβ的一个重要来源。肝脏中LRP1的减少和APP的增加可能使肝脏从Aβ的清除者或低产生者转变为外周Aβ的重要来源，这可能会影响大脑。在灌胃酒精喂养的第一周就观察到肝脏中LRP1的下调和APP的上调，并且在其他酒精喂养模型（美国国立酒精滥用与酒精中毒研究所暴饮酒精模型和对大鼠进行灌胃酒精喂养）中也出现这种情况。肝脏中LRP1和APP的调节似乎并非酒精特异性的，因为具有显著脂肪变性的ob/ob小鼠肝脏中LRP1也减少且APP表达增加。这些发现表明，肝脏脂肪变性而非酒精诱导的肝损伤可能是肝脏中LRP1和APP调节的原因。肥胖和饮酒都与AD有关，我们的数据表明，与这两种情况相关的肝脏脂肪变性会调节肝脏中的LRP1和APP，从而破坏肝脏对Aβ的加工，进而促进AD的发生。
