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 (G AO) when injected centrally can decrease GSK-3β 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-3β activation, and the phosphorylated-Ser9 residue, which reduces GSK-3β 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-3β expression. Results demonstrate that peripheral administration of G AO improves learning and memory, corresponding with alterations in GSK-3β phosphorylation state. This study supports peripherally administered G AO as a viable means to mediate GSK-3β activity within the brain and a possible treatment for AD.
Show more
Keywords: Antisense, GSK-3β, learning, memory, SAMP8, tau