期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 281, 期 26, 页码 17670-17680出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M602487200
关键词
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资金
- NIA NIH HHS [R01 AG 12686, AG 05887] Funding Source: Medline
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 (A beta) metabolism in cell culture. Treatment of Chinese hamster ovary cells overexpressing amyloid precursor protein with CQ and Cu2+ or Zn2+ resulted in an similar to 85-90% reduction of secreted A beta-(1-40) and A beta-(1-42) compared with untreated controls. Analogous effects were seen in amyloid precursor protein-overexpressing neuroblastoma cells. The secreted A beta was rapidly degraded through up-regulation of matrix metalloprotease (MMP)-2 and MMP-3 after addition of CQ and Cu2+. MMP activity was increased through activation of phosphoinositol 3-kinase and JNK. CQ and Cu2+ also promoted phosphorylation of glycogen synthase kinase-3, and this potentiated activation of JNK and loss of A beta-(1-40). Our findings identify an alternative mechanism of action for CQ in the reduction of A beta deposition in the brains of CQ-treated animals and potentially in Alzheimer disease patients.
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