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Cyclohexanehexol inhibitors of Aβ aggregation prevent and reverse Alzheimer phenotype in a mouse model

Bibliographic

Year of Publication:
2006
Contact PI Name:
JoAnne McLaurin
Contact PI Affiliation:
Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada
Co-Authors:
M.E. Kierstead, M.E. Brown, C.A. Hawkes, M.H.L. Lambermon, A.L. Phinney, A.A Darabie, J.E. Cousins, J.E. French, M.F. Lan, F. Chen, S.S.N. Wong, H.T.J. Mount, P.E. Fraser, D. Westaway, P. St. George-Hyslop
Primary Reference (PubMED ID):
Funding Source:
Canadian Institutes of Health Research (CIHR)
Natural Sciences and Engineering Research Council of Canada (NSERC)
Ontario Research and Development Challenge Fund
Howard Hughes Medical Institute
Canada Foundation for Innovation
Cryptic Rite Charitable Foundations
Scottish Rite Charitable Foundation
Ontario Alzheimer Society
Study Goal and Principal Findings:

When given orally to a transgenic mouse model of Alzheimer disease, cyclohexanehexol stereoisomers inhibit aggregation of amyloid β peptide (Aβ) into high-molecular-weight oligomers in the brain and ameliorate several Alzheimer disease–like phenotypes in these mice, including impaired cognition, altered synaptic physiology, cerebral Aβ pathology and accelerated mortality. These therapeutic effects, which occur regardless of whether the compounds are given before or well after the onset of the Alzheimer disease–like phenotype, support the idea that the accumulation of Aβ oligomers has a central role in the pathogenesis of Alzheimer disease.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Scyllo-Inositol
Therapeutic Target:
beta Amyloid Peptide
Therapy Type:
Small Molecule
Therapeutic Agent:
Epi-Inositol
Therapeutic Target:
beta Amyloid Peptide
Therapeutic Notes:
Epi-cyclohexanehexol (Epi-inositol) and Scyllo-cyclohexanehexol (Scyllo-inositol) are stereoisomers of inositol.

Animal Model

Model Information:
Species:
Mouse
Model Type:
APP
Strain/Genetic Background:
C3H/B6
Species:
Mouse
Model Type:
Non-transgenic
Strain/Genetic Background:
C3H/B6

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
Behavioral
Morris Water Maze
Open Field Test
Prolonged Survival
Histopathology
beta Amyloid Load
beta Amyloid Deposits
Fibrillar beta Amyloid Deposits
Cerebral Amyloid Angiopathy (CAA)
Activated Astrocytes
Activated Microglia
Biochemical
Brain-Buffer Soluble beta Amyloid Peptide 40
Brain-Buffer Soluble beta Amyloid Peptide 42
Brain-Formic Acid Soluble beta Amyloid Peptide 42
Brain-Formic Acid Soluble beta Amyloid Peptide 40
Amyloid Precursor Protein (APP)
APP-CTFs
Brain-beta Amyloid Oligomers
Immunochemistry
Vascular beta Amyloid
Brain-beta Amyloid Oligomers
Activated Astrocytes
Activated Microglia
Biomarker
Plasma-beta Amyloid Peptides
Pharmacodynamics
Target Engagement (Reduction beta Amyloid Peptides-Plasma)
Target Engagement (Reduction beta Amyloid Peptides-Brain)
Toxicology
Survival
Mortality