Farr Susan A, Sandoval Karin E, Niehoff Michael L, Witt Ken A, Kumar Vijaya B, Morley John E
Research & Development Service, VA Medical Center, St. Louis, Missouri, USA.
Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
J Alzheimers Dis. 2016 Oct 18;54(4):1339-1348. doi: 10.3233/JAD-160416.
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.
糖原合酶激酶（GSK）-3β是一种多功能蛋白，与阿尔茨海默病（AD）的病理特征有关，包括神经原纤维缠结、β淀粉样蛋白（Aβ）水平升高和神经退行性变。我们之前已经表明，一种针对GSK-3β上Tyr 216位点的反义寡核苷酸（GAO）经脑内注射后可降低GSK-3β水平、改善学习和记忆并减轻氧化应激。此外，我们还表明GAO能够穿过血脑屏障。在此，我们分别研究了在非转基因SAMP8和转基因Tg2576（APPswe）AD模型中，外周给予GAO对学习和记忆的影响。随后对脑组织进行评估，以检测导致GSK-3β激活的磷酸化Tyr 216残基以及降低GSK-3β活性的磷酸化Ser9残基的表达变化。用厌恶T迷宫测试发现，GAO处理的SAMP8小鼠的获得和保持能力有所改善，通过新物体识别（NOR）测试发现其陈述性记忆得到改善。GAO处理的SAMP8小鼠中，磷酸化Tyr 216的表达降低，磷酸化Ser9的表达增加。Tg2576 GAO处理的小鼠在T迷宫和NOR测试中的获得和保持能力均有所改善，磷酸化Ser9的GSK-3β表达增加。结果表明，外周给予GAO可改善学习和记忆，这与GSK-3β磷酸化状态的改变相对应。本研究支持外周给予GAO作为调节脑内GSK-3β活性的可行手段以及AD的一种可能治疗方法。
