Adolescent Binge Alcohol Enhances Early Alzheimer's Disease Pathology in Adulthood Through Proinflammatory Neuroimmune Activation.
Adolescent Binge Alcohol Enhances Early Alzheimer's Disease Pathology in Adulthood Through Proinflammatory Neuroimmune Activation.
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DOI：
10.3389/fphar.2022.884170
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发表时间：
2022
影响因子：
5.6
通讯作者：
Coleman, Leon G., Jr.
中科院分区：
文献类型：
--
作者：
Barnett, Alexandra;David, Emeraghi;Rohlman, Aaron;Nikolova, Viktoriya D.;Moy, Sheryl S.;Vetreno, Ryan P.;Coleman, Leon G., Jr.
流行病学研究表明，生命早期大量饮酒与阿尔茨海默病 (AD) 的风险增加有关。然而，AD 与饮酒之间的联系机制尚未确定。大量饮酒和 AD 都具有促炎信号传导增加的特点。因此，我们假设青少年暴饮乙醇会通过促炎症信号传导增加成年后的 AD 分子和行为病理学。 3xTg-AD 小鼠模型（APPSwe、tauP301、Psen1tm1Mpm）在 6-12 个月时开始出现淀粉样蛋白 (Aβ) 和 tau 病理学特征，接受青少年间歇性乙醇治疗（AIE，5 g/kg/d，例如 P25-55），并在 P200 时评估 AD 病理介质。第二组小鼠接受 AIE +/- 米诺环素（30 mg/kg/d，IP），然后在成年后进行行为测试。行为测试和测试年龄包括：运动活动和探索（27-28周）、新物体识别（NORT，28-30周）、三腔社交和社会记忆（29-31周）、前脉冲抑制（PPI，30-32周）、具有逆转功能的莫里斯水迷宫（MWM，31-35周）和压电睡眠监测（35-37 周）。我们发现 AIE 增加了成年女性海马体中神经毒性 Aβ1-42 以及杏仁核和内嗅皮质中神经元内 Aβ1-42 的水平。 AIE 也增加了女性海马中残基 Thr181 (p-tau-181) 的磷酸化 tau 蛋白。 AIE 使女性海马体中的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中 Aβ1-42 和 p-tau-181 的水平密切相关。 AIE 导致运动活动持续减少（开放场和 NORT 习惯），增加焦虑样行为（触动性），同时降低记忆保留。 AIE 期间使用抗炎化合物米诺环素治疗可阻止杏仁核中 Aβ1-42 和海马中 p-tau-181 的持续增加，并防止 AIE 诱导的触动性和记忆丧失。总之，这些数据发现青少年暴饮乙醇通过促炎症信号传导增强了成年后的 AD 分子和行为病理学。乙醇暴露期间促炎信号传导的阻断可防止乙醇引起的对 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。
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, Psen1tm1Mpm) 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 Aβ1–42 in adult female hippocampus as well as intraneuronal Aβ1–42 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 Aβ1–42 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 Aβ1–42 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.
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青少年暴饮暴食改变了小鼠的成人脑神经递质的表达，行为，大脑区域体积和神经化学。
DOI：
10.1111/j.1530-0277.2010.01385.x
发表时间：
2011-04
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
Coleman LG Jr;He J;Lee J;Styner M;Crews FT
通讯作者：
Crews FT
影响因子：
7.8
作者：
Belfiore, Ramona;Rodin, Alexis;Oddo, Salvatore
通讯作者：
Oddo, Salvatore
DOI：
10.1097/00000374-200002000-00015
发表时间：
2000-02-01
期刊：
ALCOHOL-CLINICAL AND EXPERIMENTAL RESEARCH
影响因子：
--
作者：
Deas, D;Riggs, P;Brown, S
通讯作者：
Brown, S
影响因子：
2.9
作者：
Hoeijmakers L;Heinen Y;van Dam AM;Lucassen PJ;Korosi A
通讯作者：
Korosi A
影响因子：
3.6
作者：
Coleman, Leon Garland, Jr.;Liu, Wen;Oguz, Ipek;Styner, Martin;Crews, Fulton T.
通讯作者：
Crews, Fulton T.