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Antisense oligonucleotide against GSK-3β in brain of SAMP8 mice improves learning and memory and decreases oxidative stress: involvement of transcription factor Nrf2 and implications for Alzheimer disease


Year of Publication:
Contact PI Name:
Allan D. Butterfield
Contact PI Affiliation:
Department of Chemistry, Center of Membrane Sciences, Sanders Brown Center on Aging, University of Kentucky, Lexington, Kentucky, USA
Susan A. Farr, Jessica L. Ripley, Rukhsana Sultana, Zhaoshu Zhang, Michael L. Niehoff, Thomas L. Platt, M. Paul Murphy, John E. Morley, Vijaya Kumar
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
Edunn Biotechnology St. Louis
Study Goal and Principal Findings:

Glycogen synthase kinase (GSK)-3β is a multifunctional protein that has been implicated in the pathological characteristics of Alzheimer’s disease (AD), including the heightened levels of neurofibrillary tangles, amyloid-beta (Aβ), and neurodegeneration. In this study was used 12-month-old SAMP8 mice,an AD model,to examine the effects GSK-3β may cause regarding the cognitive impairment and oxidative stress associated with AD. To suppress the level of GSK-3β, SAMP8 mice were treated with anantisense oligonucleotide (GAO) directed at this kinase. In this studie was measured a decreased level of GSK-3β in the cortex of the mice, indicating the success of the antisense treatment. Learning and memory assessments of the SAMP8 mice were tested post-antisense treatment using an aversive T-maze and object recognition test, both of which observably improved. In cortex samples of the SAMP8 mice, decreased levels of protein carbonyl and protein-bound HNE were measured, indicating decreased oxidative stress. Nuclearfactor erythroid 2-related factor 2(Nrf2) is a transcription factor known to increase the level of many antioxidants, including glutathione-S transferase (GST), and is negatively regulated by the activity of GSK-3β. This results indicated the increased nuclear localization of Nrf2 and levelof GST, suggesting the increased activity of the transcription factor as a result of GSK-3β suppression, consistent with the decreased oxidative stress observed. Consistent with the improved learning and memory, and consistent with GSK-3b being a tau kinase, was observed decreased tau phosphorylation in brain of GAO-treated SAMP8 mice compared to that of RAO-treated SAMP8mice. Lastly, was examined the ability of GAO to cross the blood–brain barrier and determined it to be possible. The results presented in this study demonstrate that reducing GSK-3 with a phosphorothionated antisense against GSK-3 improves learning and memory, reduces oxidative stress, possibly coincident with increased levels of the antioxidant transcriptional activity of Nrf2, and decreases tau phosphorylation. This study supports the notion of GAO as a possible treatment for AD.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - Antisense
Therapeutic Agent:
Antisense Oligonucleotide Targeting GSK3beta
Therapeutic Target:
Glycogen Synthase Kinase 3 beta (GSK3 beta)

Animal Model

Model Information:
Model Type:
Accelerated Aging
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
T Maze
Object Place Recognition
Glycogen Synthase Kinase 3 beta (GSK3 beta)
4-hydroxy-2-nonenal (HNE)
Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2)
Nuclear Glycogen Synthase Kinase 3 beta (GSK3 beta)
Cytosolic-Glycogen Synthase Kinase 3 beta (GSK3 beta)
Oxidative Stress Markers
Lipid Peroxidation
Glutathione-S Transferase (GST)
Carbonyl Protein
Drug Concentration-Serum
Blood Brain Barrier Penetration
Drug Concentration-Brain
Capillary Depletion
Target Engagement (Reduction Glycogen Synthase Kinase 3 beta-Brain)