Exposure to metal ions regulates mRNA levels of APP and BACE1 in PC12 cells: Blockage by curcumin

Amyloid β peptide (Aβ), generated by proteolytic cleavage of the amyloid precursor protein (APP), play a pivotal role in the pathogenesis of Alzheimer's disease (AD). The key step in the generation of Aβ is cleavage of APP by beta-site APP-cleaving enzyme 1 (BACE1). There is increasing evidence supporting an interaction between APP, Aβ and metal ions. Both APP and Aβ affect ion homeostasis. Conversely, metal ions may interact with several AD-associated pathways involved in neurofibrillary tangle formation, secretase cleavage of APP, proteolytic degradation of Aβ and the generation of reactive oxygen species. However, the underlying mechanisms remain elusive. Here we first reported the differential effects of AD-related metal ions at subtoxic concentrations on the transcription levels of APP and BACE1 in PC12 cells. Copper (Cu²⁺, 50-100 μM) and manganese (Mn²⁺, 50-100 μM) potently increased the expression of both APP and BACE1 in a time- and concentration-dependent pattern, while zinc (Zn²⁺), iron (Fe²⁺) and aluminum (Al³⁺) did not. To uncover the mechanism(s) of the increasing expression by these ions, we observed the effects of several antioxidants and some specific inhibitors on the up-expression of APP and BACE1 by metal ions. Curcumin almost completely blocked the effects of these irons, while minocycline and sodium ferulate slightly suppressed the increased BACE1 mRNA level. Signaling pathway specific inhibitors PD98059, SB203580 and CEP11004 modestly blocked the up-transcription of APP induced by copper. These results suggest that these irons cause differential effects on the expression of APP and BACE1 in PC12 cells, and curcumin can significantly reverse their effects.