Chronic Ethanol Causes Persistent Increases in Alzheimer's Tau Pathology in Female 3xTg-AD Mice: A Potential Role for Lysosomal Impairment.
Chronic Ethanol Causes Persistent Increases in Alzheimer's Tau Pathology in Female 3xTg-AD Mice: A Potential Role for Lysosomal Impairment.
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DOI：
10.3389/fnbeh.2022.886634
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发表时间：
2022
影响因子：
3
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中科院分区：
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流行病学研究发现，大量饮酒与阿尔茨海默病（AD）风险增加有关，成年早期频繁饮酒会增加风险。重度酒精使用和AD中神经炎症的增加可能是造成这种联系的部分原因。然而，尚不清楚禁欲是否会减轻这种风险。我们假设，即使在长期戒酒后，在中年饮酒狂欢会持续增加AD病理。以进行性淀粉样蛋白（Aβ）和tau病理为特征的雄性和雌性3xTg-AD小鼠（APPSwe、tauP 301、Psen 1 tm 1 Mpm）接受慢性酒精狂欢（5g/kg/天，给药5天/停药2天，i.g.）或水在成年期（从5.5至9个月大），然后禁欲和评估在14个月大。乙醇对保护性AD基因的影响（例如，APOE和TREM 2）以及促炎基因通过PCR测量。免疫组化和western blot检测病理性tau蛋白和Aβ的表达。乙醇引起保护性AD基因的持续减少：APOE（25%减少，*p < 0.05）、TREM 2（28%，*p < 0.05）、LPL（40%，**p < 0.01）和CTSD（24%，*p < 0.05），并促进女性而非男性皮质中的促炎基因签名。同时，乙醇增加总的和过度磷酸化的tau蛋白（AT 8）在梨状皮质和海马的女性，但不是男性。AT 8的水平与APOE（R =-0.67，*p < 0.05）和TREM 2（R =-0.78，**p < 0.005）负相关，表明在发病机制中的保护作用。tau磷酸化状态的主要调节因子（GSK 3 β、PKA、PP 2A）水平无差异，表明乙醇破坏了tau的清除。因此，我们测量了乙醇对降解tau的溶酶体的影响，以及使用共免疫荧光的tau的溶酶体定位。在雌性动物中，乙醇导致海马CA 1中成熟LAMP 1溶酶体的持续减少（35%，*p < 0.05），沿着总tau增加60%（*p < 0.05）。因此，成年中期的慢性酗酒会导致女性皮质和海马脑区tau病理学的持续增强。持续性AD病理学与促炎特征增加和成熟溶酶体减少相关。这表明酒精暴露过量会增加女性AD病理进展的风险。
Epidemiological studies have found that heavy alcohol use is associated with increased risk for Alzheimer’s disease (AD), with frequent drinking earlier in adulthood increasing risk. The increases in neuroinflammation featured in both heavy alcohol use and AD may be partially responsible for this link. However, it is unknown if abstinence mitigates this risk. We hypothesized that binge ethanol during mid adult life would persistently increase AD pathology even after prolonged abstinence. Male and female 3xTg-AD mice (APPSwe, tauP301, Psen1tm1Mpm) which feature progressive amyloid (Aβ) and tau pathology, received chronic binge ethanol (5g/kg/day, 5-days-on/2-days-off, i.g.) or water during adulthood (from 5.5 to 9 months of age), followed by abstinence and assessment at 14 months of age. The effects of ethanol on protective AD genes (e.g., APOE and TREM2) as well as proinflammatory genes were measured by PCR. Levels of pathologic tau and Aβ were measured by immunohistochemistry and western blot. Ethanol caused persistent reductions in protective AD genes: APOE (25% reduction, *p < 0.05), TREM2 (28%, *p < 0.05), LPL (40%, **p < 0.01), and CTSD (24%, *p < 0.05) and promoted a proinflammatory gene signature in female, but not male cortex. Concurrently, ethanol increased total and hyperphosphorylated tau (AT8) in piriform cortex and hippocampus of females, but not males. Levels of AT8 were negatively correlated with APOE (R = –0.67, *p < 0.05) and TREM2 (R = –0.78, **p < 0.005) suggesting protective roles in pathogenesis. No differences were found in levels of main regulators of tau phosphorylation state (GSK3β, PKA, PP2A), suggesting ethanol disrupted clearance of tau. Therefore, we measured the effect of ethanol on lysosomes, which degrade tau, and lysosomal localization of tau using co-immunofluorescence. In females, ethanol caused a persistent reduction in mature LAMP1 lysosomes in CA1 of hippocampus (35%, *p < 0.05), along with a 60% increase in total tau (*p < 0.05). Thus, chronic binge ethanol during mid adult life causes a persistent enhancement of tau pathology in cortical and hippocampal brain regions of females. Persistent AD pathology was associated with an increased proinflammatory signature and a reduction of mature lysosomes. This implicates binge ethanol exposure with increased risk of AD pathologic progression in females.
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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：
10.6
作者：
Crews, Fulton T.;Qin, Liya;Sheedy, Donna;Vetreno, Ryan P.;Zou, Jian
通讯作者：
Zou, Jian
影响因子：
7.8
作者：
Belfiore, Ramona;Rodin, Alexis;Oddo, Salvatore
通讯作者：
Oddo, Salvatore
影响因子：
9.9
作者：
Devanand, D. P.;Lee, Seonjoo;Mayeux, Richard
通讯作者：
Mayeux, Richard
影响因子：
--
作者：
Crews FT;Vetreno RP
通讯作者：
Vetreno RP