Cannabidiol Modulates Brain Copper Homeostasis in Wild-Type-Like But Not Alzheimer's Disease Transgenic Female Mice: Implications for Neuroprotective Therapy.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, synaptic dysfunction, and neuroinflammation. Disrupted metal homeostasis-especially copper (Cu), zinc (Zn), and iron (Fe)-is implicated in AD pathogenesis, contributing to amyloid-beta (Aβ) aggregation and oxidative stress. Cannabidiol (CBD), a non-toxic phytocannabinoid with antioxidant and neuroprotective properties, has unclear effects on brain metal regulation. Using high-resolution laser ablation-inductively coupled plasma mass spectrometry (LA‑ICP‑MS), we quantified regional metal distributions in sagittal brain sections from 12‑month‑old female wild‑type (WT) and APP/PS1 transgenic mice treated chronically with CBD or vehicle. CBD significantly elevated whole‑brain Cu in WT mice but not in APP/PS1 mice. Although Zn and Fe concentrations did not differ significantly, effect-size trends revealed regional differences in Cu and Zn patterns across treatment groups, particularly in the hippocampus. Correlation analysis revealed coordinated inter‑regional metal regulation in WT and vehicle‑treated APP/PS1 groups, which was disrupted in CBD‑treated APP/PS1 mice. Additionally, CBD‑treated WT mice exhibited increased variance in cerebellar Cu, suggesting individual differences in response. These findings suggest that CBD influences Cu homeostasis in WT animals, though not significantly altered in transgenic animals under the conditions tested. Our results support integrating spatially resolved metallomics into preclinical AD frameworks and highlight the utility of metrics beyond mean concentration-such as regional ratios, correlation structures, and variability-for detecting subtle treatment effects.