Authors
Paul A Adlard, Robert A Cherny, David I Finkelstein, Elisabeth Gautier, Elysia Robb, Mikhalina Cortes, Irene Volitakis, Xiang Liu, Jeffrey P Smith, Keyla Perez, Katrina Laughton, Qiao-Xin Li, Susan A Charman, Joseph A Nicolazzo, Simon Wilkins, Karolina Deleva, Toni Lynch, Gaik Kok, Craig W Ritchie, Rudolph E Tanzi, Roberto Cappai, Colin L Masters, Kevin J Barnham, Ashley I Bush
Publication date
2008/7/10
Journal
Neuron
Volume
59
Issue
1
Pages
43-55
Publisher
Elsevier
Description
As a disease-modifying approach for Alzheimer's disease (AD), clioquinol (CQ) targets β-amyloid (Aß) 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 Aß, 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 Aß 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 Aß reactions, and blood-brain barrier permeability are indices that predict a potential disease-modifying drug for AD. The speed of …
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Scholar articles
PA Adlard, RA Cherny, DI Finkelstein, E Gautier… - Neuron, 2008