Copper Induces Cognitive Impairment in Mice via Modulation of Cuproptosis and CREB Signaling

It has been reported that disordered Cu metabolism is associated with several neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). However, the underlying mechanism is still unclear. In this study, 4-week-old male mice were exposed to Cu by free-drinking water for three months. Then, the effects of Cu on cognitive functions in mice were tested by Morris water maze tests, and the potential mechanisms were investigated by the ELISA, immunochemistry, TUNEL, and Western blot tests. It was found that Cu exacerbates learning and memory impairment, and leads to Cu-overload in the brain and urine of mice. The results showed that Cu induces neuronal degeneration and oxidative damage, promotes the expression of apoptosis-related protein Bax, cuproptosis-related proteins FDX1 and DLAT and the proteotoxic stress marker HSP70, and decreases Fe-S cluster proteins. In addition, Cu affects the pre-synaptic and post-synaptic regulatory mechanisms through inhibiting the expression of PSD-95 and SYP. Cu also suppresses phosphorylation levels in CREB and decreases the expression of BDNF and TrkB in the mouse hippocampus. In conclusion, Cu might mediate cuproptosis, damage synaptic plasticity and inhibit the CREB/BDNF pathway to cause cognitive dysfunction in mice.