Downregulation of Parahippocampal Copper Chaperone for Superoxide Dismutase in Alzheimer's Disease.

BACKGROUND/OBJECTIVES: Proper regulation of copper is essential for maintaining neuronal stability and is facilitated by several chaperone proteins, protecting cells from oxidative damage that would otherwise be caused by improperly regulated copper ions. Oxidative stress, resulting from such dysregulation, is hypothesized to play a significant role in the pathogenesis of Alzheimer's disease (AD). METHODS: In this study, we evaluated the concentrations of the copper chaperones CCS, DCTN4, and ATOX1 in control and AD cases via Western blotting and ELISA, and quantified the copper concentrations in fractionated neurons using ICP-MS. RESULTS: Our findings reveal a significant reduction in CCS levels in AD cases (p = 0.0085), with a progressive decline observed with advancing age. This decline was more pronounced in women, although the difference did not reach statistical significance (p = 0.0768). No significant differences were observed in copper concentrations within synaptosomal (p = 0.3869) or cytosolic fractions (p = 0.4461) between the AD and control cases. Additionally, comprehensive analyses of the effects of sex and age showed no significant impact on the levels of copper chaperones or copper distribution across cellular compartments. CONCLUSIONS: These results suggest a strong association between reduced CCS levels and AD pathology, highlighting a potential role for CCS in the redistribution of copper ions within neurons. This redistribution may contribute to oxidative stress and neuronal dysfunction, offering new insights into the mechanisms underlying AD pathogenesis.