Degradation of the Alzheimer disease amyloid β-peptide by metal-dependent up-regulation of metalloprotease activity

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White, Anthony R ORCID: 0000-0003-1802-9891, Du, Tai, Laughton, Katrina M, Volitakis, Irene, Sharples, Robyn A, Xilinas, Michael E, Hoke, David E, Holsinger, RM Damian ORCID: 0000-0002-4447-0835, Evin, Genevie`ve, Cherny, Robert A, Hill, Andrew F ORCID: 0000-0001-5581-2354, Barnham, Kevin J ORCID: 0000-0003-1164-9465, Li, Qiao-Xin, Bush, Ashley I ORCID: 0000-0001-8259-9069 and Masters, Colin L ORCID: 0000-0003-3072-7940 (2006) Degradation of the Alzheimer disease amyloid β-peptide by metal-dependent up-regulation of metalloprotease activity. Journal of Biological Chemistry, 281 (26). pp. 17670-17680. ISSN 0021-9258


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 β-peptide (Aβ) metabolism in cell culture. Treatment of Chinese hamster ovary cells overexpressing amyloid precursor protein with CQ and Cu2+ or Zn2+ resulted in an ∼85-90% reduction of secreted Aβ-(1-40) and Aβ-(1-42) compared with untreated controls. Analogous effects were seen in amyloid precursor protein-overexpressing neuroblastoma cells. The secreted Aβ 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 Aβ-(1-40). Our findings identify an alternative mechanism of action for CQ in the reduction of Aβ deposition in the brains of CQ-treated animals and potentially in Alzheimer disease patients.

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Item type Article
DOI 10.1074/jbc.M602487200
Official URL
Subjects Current > FOR (2020) Classification > 3207 Medical microbiology
Current > Division/Research > Chancellery
Keywords biometals, Alzheimer's disease, AD, clioquinol, cell culture, neuroblastoma cells
Citations in Scopus 266 - View on Scopus
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