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Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta.
Neuron. 2008 Jul 10; 59(1):43-55.N

Abstract

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.

Authors+Show Affiliations

Oxidation Biology Laboratory, The Mental Health Research Institute of Victoria, Parkville, Victoria 3052, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18614028

Citation

Adlard, Paul A., et al. "Rapid Restoration of Cognition in Alzheimer's Transgenic Mice With 8-hydroxy Quinoline Analogs Is Associated With Decreased Interstitial Abeta." Neuron, vol. 59, no. 1, 2008, pp. 43-55.
Adlard PA, Cherny RA, Finkelstein DI, et al. Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta. Neuron. 2008;59(1):43-55.
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., ... Bush, A. I. (2008). Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta. Neuron, 59(1), 43-55. https://doi.org/10.1016/j.neuron.2008.06.018
Adlard PA, et al. Rapid Restoration of Cognition in Alzheimer's Transgenic Mice With 8-hydroxy Quinoline Analogs Is Associated With Decreased Interstitial Abeta. Neuron. 2008 Jul 10;59(1):43-55. PubMed PMID: 18614028.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta. AU - Adlard,Paul A, AU - Cherny,Robert A, AU - Finkelstein,David I, AU - Gautier,Elisabeth, AU - Robb,Elysia, AU - Cortes,Mikhalina, AU - Volitakis,Irene, AU - Liu,Xiang, AU - Smith,Jeffrey P, AU - Perez,Keyla, AU - Laughton,Katrina, AU - Li,Qiao-Xin, AU - Charman,Susan A, AU - Nicolazzo,Joseph A, AU - Wilkins,Simon, AU - Deleva,Karolina, AU - Lynch,Toni, AU - Kok,Gaik, AU - Ritchie,Craig W, AU - Tanzi,Rudolph E, AU - Cappai,Roberto, AU - Masters,Colin L, AU - Barnham,Kevin J, AU - Bush,Ashley I, PY - 2007/12/05/received PY - 2008/05/13/revised PY - 2008/06/25/accepted PY - 2008/7/11/pubmed PY - 2008/8/13/medline PY - 2008/7/11/entrez SP - 43 EP - 55 JF - Neuron JO - Neuron VL - 59 IS - 1 N2 - 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. SN - 1097-4199 UR - https://www.unboundmedicine.com/medline/citation/18614028/Rapid_restoration_of_cognition_in_Alzheimer's_transgenic_mice_with_8_hydroxy_quinoline_analogs_is_associated_with_decreased_interstitial_Abeta_ DB - PRIME DP - Unbound Medicine ER -