Chandrashekar Devaraj V, Jagadeesan Nataraj, Abdullah Tamara, Chang Rudy, Steinberg Ross A, Sanchez Frankey, Khal Elias, Yang Joshua, Cribbs David H, Han Derick, Sumbria Rachita K
Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, United States.
School of Pharmacy and Health Sciences, Keck Graduate Institute, Claremont, CA, United States.
Front Aging Neurosci. 2025 Mar 24;17:1526571. doi: 10.3389/fnagi.2025.1526571. eCollection 2025.
Chronic alcohol drinking is a modifiable risk factor for Alzheimer's disease (AD), but underlying mechanisms remain poorly understood. Most studies of alcohol feeding to AD mice have utilized young mice and delivered alcohol in drinking water without controlling nutritional intake.
To study the impact of Lieber-DeCarli (LDC) liquid alcohol diet, which balances nutritional intake, on AD pathology of aged Tg2576 and wild-type (WT) mice, which is unexplored.
13-month-old male and female Tg2576 or WT mice were fed LDC diet (5% ethanol or control) for six weeks ( = 11-13/group). Exploration (open-field test) and spatial reference memory (Y-maze test) were assessed after six weeks, and brains and livers were studied for Aβ levels, and Aβ synthesis and transport proteins (APP and LRP-1). Neuroinflammation, blood-brain barrier function, and synaptic health were studied using immunoassays.
LDC alcohol feeding significantly reduced survival ( < 0.05) and spatial memory ( < 0.05) in Tg2576 mice, but not in WT mice. Alcohol feeding increased ( < 0.001) insoluble endogenous mouse Aβ and reduced microgliosis ( < 0.05) in Tg2576 mice brains, but not in WT mice. LDC alcohol feeding to Tg2576 mice caused mild liver injury, and important amyloidosis-relevant hepatic proteins (LRP-1 and APP) were largely unaltered. However, brain Aβ and microgliosis were positively correlated ( < 0.05) with serum alanine aminotransferase, a marker of liver injury, in Tg2576 mice.
Chronic alcohol intake, resulting in mild liver injury, caused modest but significant AD-relevant changes in aged Tg2576 mice, which correlated with liver injury; the latter suggests significant liver-brain crosstalk in an AD model of moderate alcohol intake.
长期饮酒是阿尔茨海默病（AD）的一个可改变的风险因素，但其潜在机制仍知之甚少。大多数给AD小鼠喂食酒精的研究都使用了年轻小鼠，并在饮用水中提供酒精，而没有控制营养摄入。
研究能平衡营养摄入的利伯-德卡里（LDC）液体酒精饮食对老年Tg2576和野生型（WT）小鼠AD病理的影响，这方面尚未有研究。
给13月龄的雄性和雌性Tg2576或WT小鼠喂食LDC饮食（5%乙醇或对照）六周（每组n = 11 - 13）。六周后评估探索行为（旷场试验）和空间参考记忆（Y迷宫试验），并研究大脑和肝脏中的Aβ水平以及Aβ合成和转运蛋白（APP和LRP - 1）。使用免疫测定法研究神经炎症、血脑屏障功能和突触健康状况。
LDC酒精喂养显著降低了Tg2576小鼠的存活率（P < 0.05）和空间记忆能力（P < 0.05），但对WT小鼠没有影响。酒精喂养增加了（P < 0.001）Tg2576小鼠大脑中不溶性内源性小鼠Aβ，并减少了小胶质细胞增生（P < 0.05），但对WT小鼠没有影响。给Tg2576小鼠喂食LDC酒精饮食导致轻度肝损伤，且与淀粉样变性相关的重要肝脏蛋白（LRP - 1和APP）基本未改变。然而，在Tg2576小鼠中，大脑Aβ和小胶质细胞增生与肝损伤标志物血清丙氨酸转氨酶呈正相关（P < 0.05）。
慢性酒精摄入导致轻度肝损伤，在老年Tg2576小鼠中引起了适度但显著的与AD相关的变化，且这些变化与肝损伤相关；后者表明在适度饮酒的AD模型中存在显著的肝脑相互作用。
