Selective intracellular release of copper and zinc ions from bis(thiosemicarbazonato) complexes reduces levels of Alzheimer disease amyloid-beta 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 (MII(btsc), where M=CuII or ZnII) 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 (Abeta). The CuII(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 Abeta. Treatment with complexes susceptible to intracellular reduction increased intracellular copper levels but also resulted in a dose-dependent reduction in the levels of monomeric Abeta. Treatment with less stable ZnII(btsc) complexes increased intracellular zinc levels with a subsequent dose-dependent depletion of monomeric Abeta 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 Abeta depletion induced by the MII(btsc) complexes. Inhibition of metalloproteases also partially restored Abeta levels, implicating metal-driven metalloprotease activation in the extracellular monomeric Abeta depletion. However, a role for alternative metal-induced Abeta metabolism has not been ruled out. These studies demonstrate that MII(btsc) complexes have potential for Alzheimer disease therapy.
Donnelly
Paul S
PS
School of Chemistry, The University of Melbourne, Parkville, Victoria 3010, Australia. pauld@unimelb.edu.au
Caragounis
Aphrodite
A
Du
Tai
T
Laughton
Katrina M
KM
Volitakis
Irene
I
Cherny
Robert A
RA
Sharples
Robyn A
RA
Hill
Andrew F
AF
Li
Qiao-Xin
QX
Masters
Colin L
CL
Barnham
Kevin J
KJ
White
Anthony R
AR
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001682:Biological Availability; D016466:CHO Cells; D003300:Copper / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D015870:Gene Expression; D006801:Humans; D010084:Oxidation-Reduction / Q000187:drug effects; D013882:Thiosemicarbazones / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D015032:Zinc / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
D016564:Amyloid beta-Protein Precursor; D013882:Thiosemicarbazones; D003300:Copper; D015032:Zinc