Barnett Alexandra, David Emeraghi, Rohlman Aaron, Nikolova Viktoriya D, Moy Sheryl S, Vetreno Ryan P, Coleman Leon G
Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, United States.
Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, United States.
Front Pharmacol. 2022 Apr 26;13:884170. doi: 10.3389/fphar.2022.884170. eCollection 2022.
Epidemiological studies suggest that heavy alcohol use early in life is associated with increased risk for Alzheimer's disease (AD). However, mechanisms connecting AD with alcohol use have not been identified. Both heavy alcohol use and AD feature increased proinflammatory signaling. Therefore, we hypothesized that adolescent binge ethanol would increase AD molecular and behavioral pathology in adulthood through proinflammatory signaling. The 3xTg-AD mouse model (APPSwe, tauP301, Psen1) which features amyloid (Aβ) and tau pathology beginning at 6-12 months underwent adolescent intermittent ethanol (AIE, 5 g/kg/d, i.g., P25-55) with assessment of AD pathologic mediators at P200. A second group of mice received AIE +/- minocycline (30 mg/kg/d, IP) followed by behavioral testing in adulthood. Behavioral testing and age of testing included: locomotor activity and exploration (27-28 weeks), novel object recognition (NORT, 28-30 weeks), 3-chamber sociability and social memory (29-31 weeks), prepulse inhibition (PPI, 30-32 weeks), Morris Water Maze with reversal (MWM, 31-35 weeks), and Piezo sleep monitoring (35-37 weeks). We found that AIE increased levels of neurotoxic Aβ in adult female hippocampus as well as intraneuronal Aβ in amygdala and entorhinal cortex. Phosphorylated tau at residue Thr181 (p-tau-181) was also increased in female hippocampus by AIE. Several proinflammatory genes were persistently increased by AIE in the female hippocampus, including IL-1β, MCP-1, IL-6, and IFNα. Expression of these genes was strongly correlated with the levels of Aβ and p-tau-181 in hippocampus. AIE caused persistent decreases in locomotor activity (open-field and NORT habituation) and increased anxiety-like behavior (thigmotaxis) while reducing memory retention. Treatment with the anti-inflammatory compound minocycline during AIE blocked persistent increases in Aβ in amygdala and p-tau-181 in hippocampus, and prevented AIE-induced thigmotaxis and memory loss. Together, these data find that adolescent binge ethanol enhances AD molecular and behavioral pathology in adulthood through proinflammatory signaling. Blockade of proinflammatory signaling during ethanol exposure prevents ethanol-induced effects on pathologic accumulation of AD-associated proteins and persistent behavior changes relevant to human AD.
流行病学研究表明，早年大量饮酒与患阿尔茨海默病（AD）的风险增加有关。然而，将AD与饮酒联系起来的机制尚未明确。大量饮酒和AD都具有促炎信号增强的特征。因此，我们假设青少年暴饮乙醇会通过促炎信号在成年期增加AD的分子和行为病理学表现。3xTg-AD小鼠模型（APPSwe、tauP301、Psen1）在6至12个月时开始出现淀粉样蛋白（Aβ）和tau病理学特征，对其进行青少年间歇性乙醇处理（AIE，5 g/kg/d，腹腔注射，P25 - 55），并在P200评估AD病理介质。第二组小鼠接受AIE ± 米诺环素（30 mg/kg/d，腹腔注射）处理，随后在成年期进行行为测试。行为测试及测试年龄包括：运动活动和探索（27 - 28周）、新物体识别（NORT，28 - 30周）、三室社交性和社会记忆（29 - 31周）、前脉冲抑制（PPI，30 - 32周）、带反转的莫里斯水迷宫（MWM，31 - 35周）以及压电睡眠监测（35 - 37周）。我们发现，AIE增加了成年雌性小鼠海马体中神经毒性Aβ的水平，以及杏仁核和内嗅皮质中神经元内Aβ的水平。AIE还使雌性小鼠海马体中苏氨酸181位点的磷酸化tau（p-tau-181）增加。AIE使雌性小鼠海马体中几种促炎基因持续增加，包括IL-1β、MCP-1、IL-6和IFNα。这些基因的表达与海马体中Aβ和p-tau-181的水平密切相关。AIE导致运动活动持续下降（旷场试验和NORT习惯化），焦虑样行为增加（趋触性），同时降低记忆保持能力。在AIE期间用抗炎化合物米诺环素治疗可阻止杏仁核中Aβ和海马体中p-tau-181的持续增加，并预防AIE诱导的趋触性和记忆丧失。总之，这些数据表明青少年暴饮乙醇通过促炎信号在成年期增强AD的分子和行为病理学表现。在乙醇暴露期间阻断促炎信号可预防乙醇对AD相关蛋白病理积累的影响以及与人类AD相关的持续行为变化。
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