Manjia Zheng, Ziwei Chen, Jiling Xie, Qiyuan Yang, Minhua Mo, Liangjiao Chen

Department of Orthodontics, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction & Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou, People’s Republic of China

Correspondence: Liangjiao Chen, Department of Orthodontics, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction & Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, No. 31 huangsha Road, Guangzhou, Guangdong, 510145, People’s Republic of China, Email 2010686017@gzhmu.edu.cn

Background: The cerebral cortex is the foundation of cognitive function, and an imbalance in copper homeostasis in the cerebral cortex may cause cognitive and memory dysfunction. Metal exposure may disrupt copper (Cu) homeostasis in cells, leading to cognitive impairment. Yttrium oxide nanoparticles (Y2O3 NPs) are widely used in the biomedical field and have potential neurotoxicity. However, the influence of Y2O3 NPs on cognitive memory function in the brain is currently unclear.
Methods: The effects of Y2O3 NPs on cognitive and memory function were evaluated by rat behavioural experiments after intraperitoneal injection in a rat model. Subsequently, histological analysis was conducted on the cerebral cortex, and the Cu content and expression levels of cuproptosis-related proteins were detected both in vitro and in vivo. Finally, the copper output protein Cu transporting alpha polypeptide (ATP7A) was screened and detected at the mRNA and protein levels. Plasmid transfection experiments further confirmed that Y2O3 NPs mediate disordered Cu output through ATP7A.
Results: Y2O3 NP exposure induced cognitive and memory dysfunction in rats. This effect was related to the disruption of copper homeostasis in neuronal cells caused by Y2O3 NPs, which induced cuproptosis. Further research revealed that Y2O3 NPs downregulate ATP7A expression, thus disrupting copper output and inducing cuproptosis.
Conclusion: Y2O3 NPs induce cognitive and memory dysfunction by mediating the disruption of copper output in neuronal cells, revealing the toxicity of Y2O3 NPs to neurons. These findings contribute to their safe application in the biomedical field.

Keywords: Yttrium oxide nanoparticles, neurotoxicity, neuronal cells, copper homeostasis, cuproptosis