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: Susan A Farr, Karin E Sandoval, Michael L Niehoff, Ken A Witt, Vijaya B Kumar, John E Morley
• Journal: Journal of Alzheimer's disease : JAD (J Alzheimers Dis) Vol. 54 Issue 4 Pg. 1339-1348 (10 18 2016) ISSN: 1875-8908 [Electronic] Netherlands
• PMID: 27589526 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Oligonucleotides, Antisense
• Glycogen Synthase Kinase 3 beta

Topics

• Alzheimer Disease (drug therapy, enzymology, pathology)
• Animals
• Cellular Senescence (drug effects, physiology)
• Disease Models, Animal
• Glycogen Synthase Kinase 3 beta (antagonists & inhibitors, metabolism)
• Male
• Maze Learning (drug effects, physiology)
• Memory (drug effects, physiology)
• Mice
• Mice, Transgenic
• Oligonucleotides, Antisense (administration & dosage)