Background

Copper (Cu) is an essential metal mediating a variety of vital biological reactions with its redox property. Its dyshomeostasis has been associated with accelerated cognitive decline and neurodegenerative disorders, such as Alzheimer’s disease (AD). However, underlying neurotoxic mechanisms elicited by dysregulated Cu remain largely elusive. We and others previously demonstrated that exposure to Cu in drinking water significantly exacerbated pathological hallmarks of AD and pro-inflammatory activation of microglia, coupled with impaired phagocytic capacity, in mouse models of AD.

Methods

In the present study, we extended our investigation to evaluate whether chronic Cu exposure to wild-type (WT) and J20 mouse model of AD perturbs homeostatic dynamics of microglia and contributes to accelerated transformation of microglia towards degenerative phenotypes that are closely associated with neurodegeneration. We further looked for evidence of alterations in the microglial morphology and spatial memory of the Cu-exposed mice to assess the extent of the Cu toxicity.

Results

We find that chronic Cu exposure to pre-pathological J20 mice upregulates the translation of degenerative genes and represses homeostatic genes within microglia even in the absence amyloid-beta plaques. We also observe similar expression signatures in Cu-exposed WT mice, suggesting that excess Cu exposure alone could lead to perturbed microglial homeostatic phenotypes and contribute to accelerated cognitive decline.

Conclusion

Our findings highlight the risk of chronic Cu exposure on cognitive decline and altered microglia activation towards degenerative phenotypes. These changes may represent one of the key mechanisms linking Cu exposure or its dyshomeostasis to an increased risk for AD.

中文翻译：

---

慢性铜暴露将小胶质细胞导向阿尔茨海默病野生型和 J20 小鼠模型中的退行性表达特征。

背景

铜 (Cu) 是一种必不可少的金属，具有氧化还原特性，可介导各种重要的生物反应。它的体内平衡失调与加速的认知能力下降和神经退行性疾病有关，例如阿尔茨海默病 (AD)。然而，由失调的铜引起的潜在神经毒性机制在很大程度上仍然难以捉摸。我们和其他人先前证明，在 AD 小鼠模型中，暴露于饮用水中的 Cu 会显着加剧 AD 的病理特征和小胶质细胞的促炎性激活，并伴有吞噬能力受损。

方法

在本研究中，我们扩展了我们的研究，以评估慢性铜暴露于 AD 的野生型 (WT) 和 J20 小鼠模型是否会扰乱小胶质细胞的稳态动力学，并有助于加速小胶质细胞向与神经变性密切相关的退行性表型的转变。我们进一步寻找暴露于铜的小鼠的小胶质细胞形态和空间记忆改变的证据，以评估铜毒性的程度。

结果

我们发现，即使在没有淀粉样蛋白斑块的情况下，慢性铜暴露于病理前 J20 小鼠也会上调退化基因的翻译并抑制小胶质细胞内的稳态基因。我们还在暴露于铜的 WT 小鼠中观察到类似的表达特征，表明单独过量暴露铜可能导致小胶质细胞稳态表型受到干扰，并导致认知能力加速下降。

结论

我们的研究结果强调了慢性铜暴露对认知能力下降和小胶质细胞活化向退行性表型的改变的风险。这些变化可能代表了将铜暴露或其体内平衡失调与 AD 风险增加联系起来的关键机制之一。