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

被引：588

作者：

Adlard, Paul A. ^{[1
,2
]}

Cherny, Robert A. ^{[1
,2
,5
]}

Finkelstein, David I. ^{[1
,3
]}

Gautier, Elisabeth ^{[5
]}

Robb, Elysia ^{[1
]}

Cortes, Mikhalina ^{[1
]}

Volitakis, Irene ^{[1
]}

Liu, Xiang ^{[1
]}

Smith, Jeffrey P. ^{[1
]}

Perez, Keyla ^{[1
]}

Laughton, Katrina ^{[1
,2
]}

Li, Qiao-Xin ^{[1
,2
]}

Charman, Susan A. ^{[6
]}

Nicolazzo, Joseph A. ^{[6
]}

Wilkins, Simon ^{[1
,3
]}

Deleva, Karolina ^{[1
]}

Lynch, Toni ^{[1
]}

Kok, Gaik ^{[5
]}

Ritchie, Craig W. ^{[7
]}

Tanzi, Rudolph E. ^{[8
]}

Cappai, Roberto ^{[1
,2
,4
]}

Masters, Colin L. ^{[1
,3
]}

Barnham, Kevin J. ^{[1
,2
,4
]}

Bush, Ashley I. ^{[1
,2
]}

机构：

[1] Mental Hlth Res Inst, Oxidat Biol Lab, Parkville, Vic 3052, Australia

[2] Univ Melbourne, Dept Pathol, Melbourne, Vic 3010, Australia

[3] Univ Melbourne, Ctr Neurosci, Melbourne, Vic 3010, Australia

[4] Univ Melbourne, Bio Mol Sci & Biotechnol Inst 21, Melbourne, Vic 3010, Australia

[5] Prana Biotechnol Ltd, Parkville, Vic 3052, Australia

[6] Monash Univ, Monash Inst Pharmaceut Sci, Ctr Drug Candidate Optimisat, Parkville, Vic 3052, Australia

[7] UCL Royal Free & Univ Coll Med Sch, Dept Mental Hlth Sci, Metab & Clin Trials Unit, London WC1E 6BT, England

[8] Massachusetts Gen Hosp, Genet & Aging Res Unit, Charlestown, MA 02129 USA

来源：

NEURON | 2008年 / 59卷 / 01期

基金：

英国医学研究理事会; 澳大利亚研究理事会;

关键词：

D O I：

10.1016/j.neuron.2008.06.018

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

As a disease-modifying approach for Alzheimer's disease (AD), clioquinol (CQ) targets beta-amyloid (A beta) 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 AB, 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 AB 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 AB 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.

引用

页码：43 / 55

页数：13

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