Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta.
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.
Adlard
Paul A
PA
Oxidation Biology Laboratory, The Mental Health Research Institute of Victoria, Parkville, Victoria 3052, Australia.
Cherny
Robert A
RA
Finkelstein
David I
DI
Gautier
Elisabeth
E
Robb
Elysia
E
Cortes
Mikhalina
M
Volitakis
Irene
I
Liu
Xiang
X
Smith
Jeffrey P
JP
Perez
Keyla
K
Laughton
Katrina
K
Li
Qiao-Xin
QX
Charman
Susan A
SA
Nicolazzo
Joseph A
JA
Wilkins
Simon
S
Deleva
Karolina
K
Lynch
Toni
T
Kok
Gaik
G
Ritchie
Craig W
CW
Tanzi
Rudolph E
RE
Cappai
Roberto
R
Masters
Colin L
CL
Barnham
Kevin J
KJ
Bush
Ashley I
AI
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000187:drug effects / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D045744:Cell Line, Tumor; D007464:Clioquinol; D003071:Cognition / Q000187:drug effects*; D003300:Copper / Q000494:pharmacology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D006912:Hydroxyquinolines / Q000627:therapeutic use*; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009447:Neuroblastoma; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D015032:Zinc / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D006912:Hydroxyquinolines; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); D003300:Copper; D007464:Clioquinol; D015032:Zinc