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Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer’s disease transgenic mice

BIBLIOGRAPHIC THERAPEUTIC AGENT ANIMAL MODEL EXPERIMENTAL DESIGN OUTCOMES

Bibliographic

Year of Publication:
2001
Contact PI Name:
Ashley I. Bush
Contact PI Affiliation:
Department of Pathology, The University of Melbourne and, The Mental Health Research Institute of Victoria, Australia
Co-Authors:
R.A. Cherny, C.S. Atwood, M.E. Xilinas, D.N. Gray, W.D. Jones, C.A. McLean, K.J. Barnham, I. Volitakis, F.W. Fraser, Y. Kim, X. Huang, L.E. Goldstein, R.D. Moir, J.T. Lim, K. Beyreuther, H. Zheng, R.E. Tanzi, C.L. Masters
Primary Reference (PubMED ID):
11430801
Funding Source:
Prana Biotechnology Ltd.
National Institute on Aging (NIA)
Percy Baxter Charitable Trust
American Health Assistance Foundation
National Health and Medical Research Council of Australia
Study Goal and Principal Findings:

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.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Clioquinol
PubMed
PubChem
DrugBank
ClinicalTrials
Patents
Therapeutic Target:
Metal Ions - Copper
Open Targets
Therapeutic Target:
Metal Ions - Zinc
Open Targets

Animal Model

Model Information:
Species:
Mouse
Model Type:
APP
Model Name:
Tg2576
ALZFORUM
Strain/Genetic Background:
B6SJLF1/J

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Biomarkers
Dose
Formulation
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest

Outcomes

Outcome Measured
Outcome Parameters
Histopathology
beta Amyloid Deposits
beta Amyloid Load
Biochemical
beta Amyloid Aggregation
Amyloid Precursor Protein (APP)
Brain-Buffer Insoluble beta Amyloid Peptide 40
Brain-Buffer Insoluble beta Amyloid Peptide 42
Brain-Buffer Soluble beta Amyloid Peptide 40
Brain-Buffer Soluble beta Amyloid Peptide 42
Glial Fibrillary Acidic Protein (GFAP)
Synaptophysin
Serum-beta Amyloid Peptides
Metal Quantification
Immunochemistry
Brain-beta Amyloid Deposits
Spectroscopy
Nuclear Magnetic Resonance Spectroscopy
Biomarker
Serum-beta Amyloid Peptides
Pharmacodynamics
Target Engagement (Reduction Metals)
Toxicology
General Behavior
Body Weight
Survival
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