Rapid restoration of cognition in alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta

Paul A Adlard, Robert A Cherny, David I Finklestein, Elisabeth Gautier, Elysia Robb, Mikhalina Cortes, Irene Volitakis, Xiang Liu, Jeffrey P Smith, Keyla Perez, Katrina M Laughton, Qiao-Xin Lin, Susan Ann Charman, Joseph Nicolazzo, Simon Jeremy Wilkins, Karolina Deleva, Toni Lynch, Gaik Kok, Craig W Ritchie, Rudolph E TanziRoberto Cappai, Colin Louis Masters, Kevin Jeffrey Barnham, Ashley I Bush

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540 Citations (Scopus)

Abstract

As a diease-modifying approach for Alzheimer s disease (AD), clioquinol 9CQ) targets beta-amyloid (ABeta) reactions with synaptic Zn and Cu yet promotes meatl uptake. Here we characterise the second-generation 8-hydroxy quinoline analog PBT2, which also targets metal-induced aggregation of ABeta, but it more effective as a Zn/Cu ionophore and has greater blood-brain barrier permeability. Given orally to two types of amyloid-bearing transgenic mouse moelds of AD, PBT2 outperformed CQ by markedly decreasing soluble interstitial brain Abeta withon hours and improving cognitive performance to exceed that of normal littermate controls within days. Nontransgenic mice were unaffected by PBT2. The current data deomostrate that ionophore activity, inhibition of in vitro metal-mediated Abeta reactions, and blood-brain barrie permeability are indices that predict a potential disease-modifying drug for AD. The speed of recovery of the animals underscores the acutely reversible nautre of the cognitive deficits associated with transgenic models of AD.
Original languageEnglish
Pages (from-to)43 - 55
Number of pages13
JournalNeuron
Volume59
Publication statusPublished - 2008

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