Peripheral Administration of GSK-3β Antisense Oligonucleotide Improves Learning and Memory in SAMP8 and Tg2576 Mouse Models of Alzheimer's Disease

Glycogen synthase kinase (GSK)-3 beta 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 (A beta), and neurodegeneration. We have previously shown that an antisense oligonucleotide directed at the Tyr 216 site on GSK-3 beta ((G)AO) when injected centrally can decrease GSK-3 beta levels, improve learning and memory, and decrease oxidative stress. In addition, we showed that (G)AO can cross the blood-brain barrier. Herein the impact of peripherally administered (G)AO 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-3 beta activation, and the phosphorylated-Ser9 residue, which reduces GSK-3 beta activity. SAMP8 (G)AO-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 (G)AO-treated SAMP8 mice. Tg2576 (G)AO-treated mice improved acquisition and retention in both the T-maze and NOR tests, with an increased phosphorylated-Ser9 GSK-3 beta expression. Results demonstrate that peripheral administration of (G)AO improves learning and memory, corresponding with alterations in GSK-3 beta phosphorylation state. This study supports peripherally administered (G)AOas a viable means to mediate GSK-3 beta activity within the brain and a possible treatment for AD.