Affiliations: [a]
Research & Development Service, VA Medical Center, St. Louis, Missouri, USA
| [b]
Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, Missouri, USA
| [c]
Pharmaceutical Sciences, School of Pharmacy, Southern Illinois University Edwardsville, Edwardsville, Illinois, USA
| [d]
Division of Endocrinology, Saint Louis University School of Medicine, St. Louis, Missouri, USA
Correspondence:
[*]
Correspondence to: Susan A. Farr, PhD, Research Health Scientist/Professor, VA Medical Center St. Louis, MO/Division of Geriatric Medicine, St. Louis University School of Medicine, 915 North Grand Blvd 151/JC, St. Louis, MO 63106, USA. E mail: farrsa@slu.edu.
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.
Keywords: Antisense, GSK-3β, learning, memory, SAMP8, tau
