Selective intracellular release of copper and zinc ions from bis( thiosemicarbazonato) complexes reduces levels of Alzheimer disease amyloid-β peptide

Copper and zinc play important roles in Alzheimer disease pathology with recent reports describing potential therapeutics based on modulation of metal bioavailability. We examined the ability of a range of metal bis( thiosemicarbazonato) complexes (M-II(btsc), where M = Cu-II or Zn-II) to increase intracellular metal levels in Chinese hamster ovary cells overexpressing amyloid precursor protein (APP-CHO) and the subsequent effect on extracellular levels of amyloid-beta peptide (A beta). The Cu-II( btsc) complexes were engineered to be either stable to both a change in oxidation state and dissociation of metal or susceptible to intracellular reduction and dissociation of metal. Treatment of APP-CHO cells with stable complexes resulted in elevated levels of intracellular copper with no effect on the detected levels of A beta. Treatment with complexes susceptible to intracellular reduction increased intracellular copper levels but also resulted in a dose-dependent reduction in the levels of monomeric A beta. Treatment with less stable Zn-II( btsc) complexes increased intracellular zinc levels with a subsequent dose-dependent depletion of monomeric A beta levels. The increased levels of intracellular bioavailable copper and zinc initiated a signaling cascade involving activation of phosphoinositol 3-kinase and c-Jun N-terminal kinase. Inhibition of these enzymes prevented A beta depletion induced by the M-II( btsc) complexes. Inhibition of metalloproteases also partially restored A beta levels, implicating metal-driven metalloprotease activation in the extracellular monomeric A beta depletion. However, a role for alternative metal-induced A beta metabolism has not been ruled out. These studies demonstrate that MII( btsc) complexes have potential for Alzheimer disease therapy.