Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice.
Inhibition of neocortical beta-amyloid (Abeta) accumulation may be essential in an effective therapeutic intervention for Alzheimer's disease (AD). Cu and Zn are enriched in Abeta deposits in AD, which are solubilized by Cu/Zn-selective chelators in vitro. Here we report a 49% decrease in brain Abeta deposition (-375 microg/g wet weight, p = 0.0001) in a blinded study of APP2576 transgenic mice treated orally for 9 weeks with clioquinol, an antibiotic and bioavailable Cu/Zn chelator. This was accompanied by a modest increase in soluble Abeta (1.45% of total cerebral Abeta); APP, synaptophysin, and GFAP levels were unaffected. General health and body weight parameters were significantly more stable in the treated animals. These results support targeting the interactions of Cu and Zn with Abeta as a novel therapy for the prevention and treatment of AD.
Cherny
R A
RA
Department of Pathology, The University of Melbourne and, The Mental Health Research Institute of Victoria, Australia.
Atwood
C S
CS
Xilinas
M E
ME
Gray
D N
DN
Jones
W D
WD
McLean
C A
CA
Barnham
K J
KJ
Volitakis
I
I
Fraser
F W
FW
Kim
Y
Y
Huang
X
X
Goldstein
L E
LE
Moir
R D
RD
Lim
J T
JT
Beyreuther
K
K
Zheng
H
H
Tanzi
R E
RE
Masters
C L
CL
Bush
A I
AI
D000367:Age Factors; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002614:Chelating Agents / Q000494:pharmacology*; D007464:Clioquinol / Q000494:pharmacology*; D003300:Copper / Q000378:metabolism*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D016708:Synaptophysin / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D005904:Glial Fibrillary Acidic Protein; D016708:Synaptophysin; D003300:Copper; D007464:Clioquinol; D015032:Zinc