Degradation of the Alzheimer Disease Amyloid β-Peptide by Metal-dependent Up-regulation of Metalloprotease Activity

Department of Pathology, University of Melbourne, Cnr. Grattan Street and Royal Parade, Victoria 3010, Australia.
Journal of Biological Chemistry (Impact Factor: 4.57). 07/2006; 281(26):17670-80. DOI: 10.1074/jbc.M602487200
Source: PubMed


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.

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Available from: Geneviève M Evin, Nov 07, 2015
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    • "Cohen , 2001 ) , cell survival ( Takashima et al . , 1993 ) , cell motility ( Lucas et al . , 1998 ) , and memory formation ( Bradley et al . , 2012 ) . Hyperphosphorylation of tau and Ab production in AD have been linked to GSK - 3 dysfunction ( DaRocha - Souto et al . , 2012 ; Noble et al . , 2005 ; Phiel et al . , 2003 ; Pooler et al . , 2012 ; White et al . , 2006 ; Kimura et al . , 2013 ) . In double transgenic APP / tau mice , GSK - 3 inhibition ameliorates plaque - related neuritic changes , suggesting a role of this kinase in Ab - induced pathology ( DaRocha - Souto et al . , 2012 ) . However , the molecular mechanisms linking Ab oligomers toxicity to GSK - 3 are still poorly understood . Our "
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