George Mason University, Fairfax, VA, USA.
J Alzheimers Dis. 2018;64(2):617-630. doi: 10.3233/JAD-180151.
Hyperphosphorylated tau protein is a key pathology in Alzheimer's disease (AD), frontotemporal dementia, chronic traumatic encephalopathy, and Parkinson's disease. The essential trace element zinc exacerbates tauopathy in vitro as well as in a Drosophila model of AD. However, the interaction has never been assessed behaviorally or biochemically in mammals. Zinc supplementation is prevalent in society, finding use as a treatment for macular degeneration and cataracts, and is also taken as an immune system booster with high levels appearing in multivitamins marketed toward the elderly. Using a transgenic mouse model that contains the human gene for tau protein (P301L), we assessed the effects of excess chronic zinc supplementation on tau pathology. Behavioral tests included nest building, circadian rhythm, Morris Water Maze, fear conditioning, and open field. Biochemically, total tau and Ser396 phosphorylation were assessed using western blot. Number of tangles were assessed by Thioflavin-S and free zinc levels were assessed by Zinpyr-1. Tau mice demonstrated behavioral deficits compared to control mice. Zinc supplementation exacerbated tauopathic deficits in circadian rhythm, nesting behavior, and Morris Water Maze. Biochemically, zinc-supplemented tau mice showed increased phosphorylation at pSer396. Zinc supplementation in tau mice also increased tangle numbers in the hippocampus while decreasing free-zinc levels, demonstrating that tangles were sequestering zinc. These results show that zinc intensified the deficits in behavior and biochemistry caused by tau.
过度磷酸化的 tau 蛋白是阿尔茨海默病（AD）、额颞叶痴呆、慢性创伤性脑病和帕金森病的关键病理学特征。必需微量元素锌在体外以及 AD 的果蝇模型中加剧 tau 病。然而，这种相互作用在哺乳动物中从未在行为或生化方面进行过评估。锌补充剂在社会中很普遍，用于治疗黄斑变性和白内障，也被用作免疫系统增强剂，在针对老年人的多种维生素中含量很高。我们使用含有人类 tau 蛋白基因（P301L）的转基因小鼠模型，评估了过量慢性锌补充对 tau 病理学的影响。行为测试包括筑巢、昼夜节律、Morris 水迷宫、恐惧条件反射和旷场。使用 Western blot 评估总 tau 和 Ser396 磷酸化。通过 Thioflavin-S 评估缠结的数量，通过 Zinpyr-1 评估游离锌水平。与对照小鼠相比，tau 小鼠表现出行为缺陷。锌补充加剧了 tau 病昼夜节律、筑巢行为和 Morris 水迷宫的缺陷。生物化学分析表明，锌补充的 tau 小鼠在 pSer396 处的磷酸化增加。锌补充还增加了 tau 小鼠海马中的缠结数量，同时降低了游离锌水平，表明缠结正在螯合锌。这些结果表明，锌加剧了 tau 引起的行为和生化缺陷。
