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Degradation of the Alzheimer Disease Amyloid β-Peptide by Metal-dependent Up-regulation of Metalloprotease Activity
Open accessAbstract
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 Cu 2+ or Zn 2+ 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 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 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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“MMPs are known to be linked to extracellular protein degradation including Aβ (72), whereas MMPs upregulated in AD may also confer neuroinflammation, synaptic dysfunction, and neuronal death (73, 74).”
From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [72]
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Metadata
- Authors
- White, A. R., Du, T., Laughton, K. M., Volitakis, I., Sharples, R. A., Xilinas, M. E., Hoke, D. E., Holsinger, R. M. D., Evin, G., Cherny, R. A., Hill, A. F., Barnham, K. J., Li, Q.-X., Bush, A. I., & Masters, C. L.
- Affiliations
- Mental Health Research Institute (AU)
- Corresponding author
- White, Anthony R.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2006-06
- Volume
- 281
- Issue
- 26
- Pages
- 17670-17680
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2131181742
- Cited by
- 284
- References
- 44
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 10 · 2023: 6 · 2022: 4 · 2021: 10 · 2020: 17 · 2019: 5 · 2018: 6 · 2017: 11 · 2016: 13 · 2015: 18 · 2014: 16 · 2013: 12 · 2012: 21
- FWCI
- 16.39
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Victoria University Research Repository (Victoria University) (submittedVersion, cc-by)
- Funders
- National Institute on Aging (R01-AG12686, AG 05887)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, amyloid-beta, clioquinol, MMP-2, MMP-3, copper, zinc, amyloid precursor protein, phosphatidylinositol 3-kinase, JNK, glycogen synthase kinase-3, metal bioavailability, biometals
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