Xia Yiteng, Tsim Karl W K, Wang Wen-Xiong
School of Energy and Environment and State Key Laboratory of Marine Pollution, City University of Hong Kong, Kowloon, Hong Kong, China.
Research Centre for the Oceans and Human Health, City University of Hong Kong Shenzhen Research Institute, Shenzhen 518057, China.
Environ Health (Wash). 2024 Nov 13;3(3):238-249. doi: 10.1021/envhealth.4c00175. eCollection 2025 Mar 21.
Alzheimer's disease (AD) is a neurodegenerative disorder disease mainly caused by extracellular senile plaques (SP) formed by β-amyloid (Aβ1-42) protein deposits. Copper (Cu) is an essential metal involved in neural system, and its homeostasis is the key to maintain its proper function. Herein, the subcellular locations of Cu(I) and Cu(II) in human neurodegenerative disease SH-SY5Y cells and AD mouse brains were imaged. We found that the content of Cu(II) decreased while that of Cu(I) increased under Aβ exposure, which were further verified in the brain tissues of the AD mouse model, strongly suggesting the disruption of Cu homeostasis under Aβ exposure or AD. Remarkably, the mitochondrial and lysosomal Cu(II) decreased significantly, whereas Cu(I) decreased in mitochondria but increased in lysosome. Lysosomes digested the damaged mitochondria via mitophagy to remove excess Cu(I) and maintain Cu homeostasis. The Aβ induced Cu(I) in mitochondria resulted in an overformation of reactive oxygen species and altered the morphology of this organelle. Due to the oxidative stress, glutathione (GSH) was converted into glutathione disulfide (GSSG), and Cu(I) bound with GSH was further released into the cytoplasm and absorbed by the lysosome. Transcriptomic analysis showed that genes (ATP7A/B) related to Cu transportation were upregulated, whereas genes related to mitochondrial complex were down-regulated, representing the damage of this organelle. This study demonstrated that Aβ exposure caused the disruption of intracellular homeostasis by reducing Cu(II) to Cu(I) and damaging the mitochondria, which further triggered detoxification by the lysosome. Our finding provided new insights in Aβ and AD induced Cu redox transformation and toxicity.
阿尔茨海默病（AD）是一种神经退行性疾病，主要由β-淀粉样蛋白（Aβ1-42）沉积形成的细胞外老年斑（SP）引起。铜（Cu）是参与神经系统的必需金属，其稳态是维持其正常功能的关键。在此，对人类神经退行性疾病SH-SY5Y细胞和AD小鼠大脑中Cu（I）和Cu（II）的亚细胞定位进行了成像。我们发现，在Aβ暴露下，Cu（II）含量降低而Cu（I）含量增加，这在AD小鼠模型的脑组织中得到进一步验证，强烈表明在Aβ暴露或AD状态下铜稳态受到破坏。值得注意的是，线粒体和溶酶体中的Cu（II）显著降低，而线粒体中的Cu（I）降低，但溶酶体中的Cu（I）增加。溶酶体通过线粒体自噬消化受损的线粒体，以去除过量的Cu（I）并维持铜稳态。Aβ诱导线粒体中的Cu（I）导致活性氧的过度形成并改变了该细胞器的形态。由于氧化应激，谷胱甘肽（GSH）转化为谷胱甘肽二硫化物（GSSG），与GSH结合的Cu（I）进一步释放到细胞质中并被溶酶体吸收。转录组分析表明，与铜转运相关的基因（ATP7A/B）上调，而与线粒体复合物相关的基因下调，表明该细胞器受到损伤。本研究表明，Aβ暴露通过将Cu（II）还原为Cu（I）并破坏线粒体，导致细胞内稳态破坏，进而触发溶酶体的解毒作用。我们的发现为Aβ和AD诱导的铜氧化还原转化和毒性提供了新的见解。
