Disruption of Copper Redox Balance and Dysfunction under In Vivo and In Vitro Alzheimer's Disease Models

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.