title: 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.
abstract: 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 we 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 an antisense oligonucleotide (GAO) directed at this kinase. We 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. Nuclear factor 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. Our results indicated the increased nuclear localization of Nrf2 and level of 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, we observed decreased tau phosphorylation in brain of GAO-treated SAMP8 mice compared to that of RAO-treated SAMP8 mice. Lastly, we 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. Our study supports the notion of GAO as a possible treatment for AD.
authors.affiliation: Research & Development Service, VA Medical Center, St. Louis, MO, USA.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Farr
authors.affiliation: Department of Chemistry, Center of Membrane Sciences, Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40506, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Ripley
authors.affiliation: Department of Chemistry, Center of Membrane Sciences, Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40506, USA.
authors.forename: Rukhsana
authors.initials: R
authors.lastname: Sultana
authors.affiliation: Department of Chemistry, Center of Membrane Sciences, Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40506, USA.
authors.forename: Zhaoshu
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Research & Development Service, VA Medical Center, St. Louis, MO, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Niehoff
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Platt
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: M Paul
authors.initials: MP
authors.lastname: Murphy
authors.affiliation: Research & Development Service, VA Medical Center, St. Louis, MO, USA; Division of Endocrinology, Saint Louis University School of Medicine, St. Louis, MO, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Morley
authors.affiliation: Research & Development Service, VA Medical Center, St. Louis, MO, USA; Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, MO, USA.
authors.forename: Vijaya
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Department of Chemistry, Center of Membrane Sciences, Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40506, USA. Electronic address: dabcns@uky.edu.
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D000818:Animals; D001812:Blood-Brain Barrier; D002540:Cerebral Cortex / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods*; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D010364:Pattern Recognition, Visual / Q000502:physiology; D010766:Phosphorylation; D050050:Protein Carbonylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D016875:tau Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D016376:Oligonucleotides, Antisense; D017382:Reactive Oxygen Species; D016875:tau Proteins; D005982:Glutathione Transferase; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: Alzheimer’s disease (AD); Antisense; Glycogen synthase kinase-3β (GSK-3β); Nuclear factor-E2-related factor 2 (Nrf2); Oxidative stress; SAMP8 mice