Silver nanoparticles induce iron accumulation-associated cognitive impairment via modulating neuronal ferroptosis.

Silver nanoparticles (AgNPs) are widely used in daily life and medical fields owing to their unique physicochemical properties. Daily exposure to AgNPs has become a great concern regarding their potential toxicity to human beings, especially to the central nervous system. Ferroptosis, a newly recognized programmed cell death, was recently reported to be associated with the neurodegenerative process. However, whether and how ferroptosis contributes to AgNPs-induced neurotoxicity remain unclear. In this study, we investigated the role of ferroptosis in neurotoxic effects induced by AgNPs using in vitro and in vivo models. Our results showed that AgNPs induced a notable dose-dependent cytotoxic effect on HT-22 cells and cognitive impairment in mice as indicated by a decline in learning and memory and brain tissue injuries. These findings were accompanied by iron overload caused by the disruption of the iron transport system and activation of NCOA4-mediated autophagic degradation of ferritin. The excessive free iron subsequently induced GSH depletion, loss of GPX and SOD activities, differential expression of Nrf2 signaling pathway elements, down-regulation of GPX4 protein and production of lipid peroxides, initiating ferroptosis cascades. The mitigating effects of ferrostatin-1 and deferoxamine on iron overload, redox imbalance, neuronal cell death, impairment of mice learning and memory, Aβ deposition and synaptic plasticity reduction suggested ferroptosis as a potential molecular mechanism in AgNPs-induced neurotoxicity. Taken together, these results demonstrated that AgNPs induced neuronal cell death and cognitive impairment with Aβ deposition and reduction of synaptic plasticity, which were mediated by ferroptosis caused by iron-mediated lipid peroxidation. Our study provides new insights into the underlying mechanisms of AgNPs-induced neurotoxicity and predicts potential preventive strategies.