title: Peripheral Administration of GSK-3β Antisense Oligonucleotide Improves Learning and Memory in SAMP8 and Tg2576 Mouse Models of Alzheimer's 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. We have previously shown that an antisense oligonucleotide directed at the Tyr 216 site on GSK-3β (GAO) when injected centrally can decrease GSK-3β levels, improve learning and memory, and decrease oxidative stress. In addition, we showed that GAO can cross the blood-brain barrier. Herein the impact of peripherally administered GAO in both the non-transgenic SAMP8 and transgenic Tg2576 (APPswe) models of AD were examined respective to learning and memory. Brain tissues were then evaluated for expression changes in the phosphorylated-Tyr 216 residue, which leads to GSK-3β activation, and the phosphorylated-Ser9 residue, which reduces GSK-3β activity. SAMP8 GAO-treated mice showed improved acquisition and retention using aversive T-maze, and improved declarative memory as measured by the novel object recognition (NOR) test. Expression of the phosphorylated-Tyr 216 was decreased and the phosphorylated-Ser9 was increased in GAO-treated SAMP8 mice. Tg2576 GAO-treated mice improved acquisition and retention in both the T-maze and NOR tests, with an increased phosphorylated-Ser9 GSK-3β expression. Results demonstrate that peripheral administration of GAO improves learning and memory, corresponding with alterations in GSK-3β phosphorylation state. This study supports peripherally administered GAO as a viable means to mediate GSK-3β activity within the brain and a possible treatment for AD.
authors: Research & Development Service, VA Medical Center, St. Louis, Missouri, USA.|Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
authors: Susan A
authors: SA
authors: Farr
authors: Pharmaceutical Sciences, School of Pharmacy, Southern Illinois University Edwardsville, Edwardsville, Illinois, USA.
authors: Karin E
authors: KE
authors: Sandoval
authors: Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
authors: Michael L
authors: ML
authors: Niehoff
authors: Pharmaceutical Sciences, School of Pharmacy, Southern Illinois University Edwardsville, Edwardsville, Illinois, USA.
authors: Ken A
authors: KA
authors: Witt
authors: Research & Development Service, VA Medical Center, St. Louis, Missouri, USA.|Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
authors: Vijaya B
authors: VB
authors: Kumar
authors: Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, Missouri, USA.|Division of Endocrinology, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
authors: John E
authors: JE
authors: Morley
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000818:Animals; D016922:Cellular Senescence / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects* / Q000502:physiology; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage*
chemical_list: D016376:Oligonucleotides, Antisense; D000071679:Glycogen Synthase Kinase 3 beta
keywords: Antisense; GSK-3β; SAMP8; learning; memory; tau