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Pharmacological inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in bigenic tau/APP mutant mice


Year of Publication:
Contact PI Name:
David J. Vocadlo
Contact PI Affiliation:
Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada
Scott A. Yuzwa, Xiaoyang Shan, Bryan A. Jones, Gang Zhao, Melissa L. Woodward, Iaojing Li, Yanping Zhu, Ernest J. McEachern, Michael A. Silverman, Neil V. Watson, Cheng-Xin Gong
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
Alzheimer's Association
Natural Sciences and Engineering Research Council of Canada (NSERC)
Canadian Institutes of Health Research (CIHR)
Steacie Memorial Fellowship
Study Goal and Principal Findings:

In this study the authors show that Thiamet-G treatment of TAPP mice increases O-GlcNAc levels in the brain and completely prevents cognitive decline. Further, the results found that this blockade in cognitive decline is not likely due to changes in tau hyperphosphorylation or tau aggregation but rather due to alteration in the release or clearance of β-amyloid peptides, which are reflected in the number of amyloid aggregates and plaques. Using a cellular model of APP processing  the authors found that Thiamet-G does not impair release of β-amyloid peptides from APP and thus likely does not directly regulate APP processing, suggesting that O-GlcNAc probably acts at multiple other points in the β-amyloid pathological cascade. Nevertheless, OGA inhibition has positive effects on β-amyloid pathology in TAPP mice that develop synergistic tau and β-amyloid pathologies. In conclusion this study indicates that increased O-GlcNAc can influence β-amyloid pathology in the presence of tau pathology. The findings provide good support for OGA as a promising therapeutic target to alter disease progression in Alzheimer disease.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Thiamet G
Therapeutic Target:

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Not Reported

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
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


Outcome Measured
Outcome Parameters
Morris Water Maze
O-GlcNAcase Levels
Cell-beta Amyloid Peptide 42
Sarkosyl Insoluble Tau
Brain-beta Amyloid Peptide 42
Brain-beta Amyloid Peptide 40
O-GlcNAcase Levels
beta Amyloid Deposits
Target Engagement (Increased O-GlcNAcylated Protein Level)