Background:Environmental copper has been implicated in the pathogenesis of Alzheimer’s disease based on evidence that: 1) brain copper levels increase with age, 2) copper promotes misfolding and toxicity of amyloid-β in vitro, 3) copper-modulating interventions reduce amyloid pathology in animal models. However, the effect of copper upon non-amyloid Alzheimer’s pathology is relatively under-explored. Objective:To determine if modulation of brain copper level affects brain tau pathology and/or associated cognitive impairment. Methods:We tested the hypothesis that brain copper modulates tau pathology by manipulating brain levels of copper in the PS19 transgenic mouse model of tau pathology. We treated PS19 and wild-type mice with oral zinc acetate, an established therapy for long term control of excess brain copper, and examined treatment effects upon brain copper, brain tau, NFT-like pathology, and spatial memory. We treated a second cohort of mice with exogenous dietary copper in order to evaluate whether excess environmental copper promotes brain tau pathology. Results:Copper-lowering with oral zinc attenuated spatial memory impairment in female but not male PS19 mice, without a significant effect upon tau pathology. Copper loading increased brain copper, but did not have an effect on brain tau pathology or spatial memory function. Conclusion:These findings suggest that a strategy to lower brain copper may be viable for symptomatic benefit in the setting of tau neuropathology, but unlikely to have robust effects on the underlying pathology. These findings are consistent with dietary or other exogenous copper being unlikely to promote tau pathology.

中文翻译：

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抗血小板药物使用对阿尔茨海默病患者脑出血风险的影响：一项全国性队列研究。

背景：基于以下证据，环境铜与阿尔茨海默病的发病机制有关：1) 脑铜水平随年龄增加，2) 铜在体外促进淀粉样蛋白 β 的错误折叠和毒性，3) 铜调节干预减少淀粉样蛋白病理在动物模型中。然而，铜对非淀粉样蛋白阿尔茨海默病病理的影响研究相对不足。目的：确定脑铜水平的调节是否影响脑 tau 蛋白病理和/或相关的认知障碍。方法：我们通过在 PS19 转基因小鼠 tau 病理模型中操纵大脑中的铜水平来检验脑铜调节 tau 病理的假设。我们用口服醋酸锌治疗 PS19 和野生型小鼠，这是一种长期控制过量脑铜的既定疗法，并检查了对脑铜、脑 tau、NFT 样病理和空间记忆的治疗效果。我们用外源性膳食铜治疗了第二组小鼠，以评估过量的环境铜是否会促进脑 tau 蛋白病理。结果：口服锌降低铜可减轻雌性而非雄性 PS19 小鼠的空间记忆障碍，对 tau 病理学没有显着影响。铜负荷增加了脑铜，但对脑 tau 蛋白病理或空间记忆功能没有影响。结论：这些发现表明，在 tau 神经病理学背景下，降低脑铜含量的策略可能对症状有益，但不太可能对潜在病理学产生强烈影响。这些发现与饮食或其他外源性铜不太可能促进 tau 病理学一致。