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 - Finklestein, 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 M
AU - Lin, Qiao-Xin
AU - Charman, Susan Ann
AU - Nicolazzo, Joseph
AU - Wilkins, Simon Jeremy
AU - Deleva, Karolina
AU - Lynch, Toni
AU - Kok, Gaik
AU - Ritchie, Craig W
AU - Tanzi, Rudolph E
AU - Cappai, Roberto
AU - Masters, Colin Louis
AU - Barnham, Kevin Jeffrey
AU - Bush, Ashley I
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
UR - http://www.sciencedirect.com/science/article/pii/S0896627308005369
M3 - Article
VL - 59
SP - 43
EP - 55
JO - Neuron
JF - Neuron
SN - 0896-6273
ER -