Chronic lead exposure disrupts copper redox homeostasis and aggravates neurodegeneration.

Lead (Pb) represents a critical environmental health concern due to its profound impact on neurodegenerative processes. However, its specific influence on copper (Cu) redox states and the associated neurotoxic mechanisms remain inadequately understood. In this study, male wild-type C57BL/6 and 5xFAD Alzheimer's disease (AD) model mice were used to investigate how chronic low-dose Pb exposure (200 μg/L via drinking water) exacerbated AD-related pathology through perturbation of Cu homeostasis. Elemental analysis revealed that Pb exposure depleted essential cerebral metals, including Ca, Mg, Fe, and Zn. In contrast to these metals, Cu showed concurrent accumulation in both the brain and bloodstream, particularly in the ADPb group, consistent with disturbed Cu homeostasis in the AD background. In situ fluorescent imaging demonstrated that Pb exposure significantly disrupted the Cu(I)/Cu(II) valence balance within the hippocampus. While the unexposed AD brain showed relatively higher Cu(I) signals, Pb exposure shifted the fluorescence pattern toward Cu(II). Behavioral assessments further indicated that Pb exposure was associated with reduced locomotor activity, anxiety-like responses, and accelerated spatial memory decay in AD mice. Histopathological and immunofluorescence evaluations structurally confirmed these functional deficits, revealing disorganized hippocampal cytoarchitecture, myelin loss, and accelerated Aβ plaque deposition in the ADPb group. Ultimately, these findings demonstrated that environmental Pb exacerbated AD progression not solely through direct physical toxicity, but fundamentally by disrupting the in situ Cu(II)/Cu(I) redox equilibrium. This study highlights Cu redox imbalance as a potential mediator linking Pb exposure with AD progression and warrants further biochemical validation.