Rapid Restoration of Cognition in Alzheimer's Transgenic Mice with 8-Hydroxy Quinoline Analogs Is Associated with Decreased Interstitial Aβ
Open accessAbstract
As a disease-modifying approach for Alzheimer's disease (AD), clioquinol (CQ) targets beta-amyloid (Abeta) reactions with synaptic Zn and Cu yet promotes metal uptake. Here we characterize the second-generation 8-hydroxy quinoline analog PBT2, which also targets metal-induced aggregation of Abeta, but is more effective as a Zn/Cu ionophore and has greater blood-brain barrier permeability. Given orally to two types of amyloid-bearing transgenic mouse models of AD, PBT2 outperformed CQ by markedly decreasing soluble interstitial brain Abeta within hours and improving cognitive performance to exceed that of normal littermate controls within days. Nontransgenic mice were unaffected by PBT2. The current data demonstrate that ionophore activity, inhibition of in vitro metal-mediated Abeta reactions, and blood-brain barrier permeability are indices that predict a potential disease-modifying drug for AD. The speed of recovery of the animals underscores the acutely reversible nature of the cognitive deficits associated with transgenic models of AD.
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Use of non-specific chelators (i.e., CQ) that do not interact selectively with the Aβ-metal species exhibit adverse side effects that will likely limit their long term clinical use.
“However, use of non-specific chelators (i.e., CQ) that do not interact selectively with the Aβ–metal species exhibit adverse side effects that will likely limit their long term clinical use.3,28,29,31,44,46–48”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [48]
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- Authors
- Adlard, P. A., Cherny, R. A., Finkelstein, D. I., Gautier, E., Robb, E., Cortes, M., Volitakis, I., Liu, X., Smith, J. P., Perez, K., Laughton, K., Li, Q.-X., Charman, S. A., Nicolazzo, J. A., Wilkins, S., Deleva, K., Lynch, T., Kok, G., Ritchie, C. W., Tanzi, R. E., Cappai, R., Masters, C. L., Barnham, K. J., & Bush, A. I.
- Affiliations
- Mental Health Research Institute (AU)
- Prana Biotechnology (Australia) (AU)
- Monash University (AU)
- The Royal Free Hospital (GB)
- Massachusetts General Hospital (US)
- Corresponding author
- Bush, Ashley I.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2008-07
- Volume
- 59
- Issue
- 1
- Pages
- 43-55
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2055659156
- Cited by
- 672
- References
- 9
- Citations by year
- 2026: 13 · 2025: 19 · 2024: 24 · 2023: 19 · 2022: 23 · 2021: 16 · 2020: 36 · 2019: 41 · 2018: 41 · 2017: 46 · 2016: 39 · 2015: 36 · 2014: 47 · 2013: 34 · 2012: 61
- FWCI
- 40.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1878 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Australian Research Council
- National Health and Medical Research Council
- National Medical Research Council
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- Alzheimer's disease, PBT2, clioquinol, amyloid-beta, blood-brain barrier permeability, cognitive recovery, transgenic mouse model, disease-modifying therapy
- MeSH terms
- Alzheimer Disease, Analysis of Variance, Animals, Behavior, Animal, Cognition, Copper, Disease Models, Animal, Hippocampus, Humans, Hydroxyquinolines, Clioquinol, Mice, Inbred C57BL, Mice, Transgenic, Neuroblastoma, Peptide Fragments, Zinc, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Long-Term Potentiation, Maze Learning, Cell Line, Tumor, Mice, Presenilin-1, In Vitro Techniques
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