Degradation of the Alzheimer disease amyloid beta-peptide by metal-dependent up-regulation of metalloprotease activity.
Biometals play an important role in Alzheimer disease, and recent reports have described the development of potential therapeutic agents based on modulation of metal bioavailability. The metal ligand clioquinol (CQ) has shown promising results in animal models and small phase clinical trials; however, the actual mode of action in vivo has not been determined. We now report a novel effect of CQ on amyloid beta-peptide (Abeta) metabolism in cell culture. Treatment of Chinese hamster ovary cells overexpressing amyloid precursor protein with CQ and Cu(2+) or Zn(2+) resulted in an approximately 85-90% reduction of secreted Abeta-(1-40) and Abeta-(1-42) compared with untreated controls. Analogous effects were seen in amyloid precursor protein-overexpressing neuroblastoma cells. The secreted Abeta was rapidly degraded through up-regulation of matrix metalloprotease (MMP)-2 and MMP-3 after addition of CQ and Cu(2+). MMP activity was increased through activation of phosphoinositol 3-kinase and JNK. CQ and Cu(2+) also promoted phosphorylation of glycogen synthase kinase-3, and this potentiated activation of JNK and loss of Abeta-(1-40). Our findings identify an alternative mechanism of action for CQ in the reduction of Abeta deposition in the brains of CQ-treated animals and potentially in Alzheimer disease patients.
White
Anthony R
AR
Department of Pathology, University of Melbourne, Cnr. Grattan Street and Royal Parade, Victoria 3010, Australia. arwhite@unimelb.edu.au
Du
Tai
T
Laughton
Katrina M
KM
Volitakis
Irene
I
Sharples
Robyn A
RA
Xilinas
Michel E
ME
Hoke
David E
DE
Holsinger
R M Damian
RM
Evin
Geneviève
G
Cherny
Robert A
RA
Hill
Andrew F
AF
Barnham
Kevin J
KJ
Li
Qiao-Xin
QX
Bush
Ashley I
AI
Masters
Colin L
CL
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000891:Anti-Infective Agents, Local / Q000494:pharmacology; D016466:CHO Cells; D045744:Cell Line, Tumor; D007464:Clioquinol / Q000494:pharmacology; D003300:Copper / Q000493:pharmacokinetics*; D006224:Cricetinae; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D007501:Iron / Q000493:pharmacokinetics; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D051379:Mice; D009447:Neuroblastoma; D010446:Peptide Fragments / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects; D015032:Zinc / Q000493:pharmacokinetics*
D016229:Amyloid beta-Peptides; D000891:Anti-Infective Agents, Local; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D003300:Copper; D007464:Clioquinol; D007501:Iron; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D015032:Zinc