Restoration of mitochondrial homeostasis by Wnt3a/β-catenin/c-Myc alleviates cadmium-induced neural stem cell senescence and cognitive impairment in mouse hippocampus.

Cadmium (Cd), a prevalent environment heavy metal, has been associated with cognitive impairment and an increased risk of neurodegenerative diseases. However, the precise mechanisms underlying Cd-induced cognitive dysfunction remain poorly understood, particularly regarding its effects on hippocampal neural stem cells (NSCs). In this study, we identified NSC senescence as a key contributor to Cd-induced cognitive impairment using both animal and cellular models. We demonstrated that chronic exposure to environmentally relevant doses of Cd led to hippocampal-dependent cognitive deficits and accelerated NSC senescence in the subgranular zone (SGZ) of the hippocampus. Hallmarks of Cd-induced NSC senescence included reduced proliferative capacity, mitochondrial dysfunction, lysosomal hyperactivity, and nuclear morphological abnormalities. Mechanism investigations revealed that Cd disrupted the Wnt3a/β-catenin/c-Myc signaling pathway, leading to impaired mitochondrial homeostasis. Importantly, Wnt3a overexpression effectively mitigated mitochondrial damage and NSC senescence, highlighting its protective role in maintaining NSC function. Furthermore, c-Myc was identified as a key downstream mediator in Wnt3a/β-catenin-driven mitochondrial protection, linking impaired mitochondrial integrity to NSC senescence. These findings elucidate the molecular mechanisms underlying Cd-induced neurotoxicity and identify potential therapeutic targets to mitigating the adverse effects of environmental toxicants on the nervous system.