A novel glycogen synthase kinase-3 inhibitor 2-methyl-5-(3-{4-[(S)-methylsulfinyl]phenyl}-1-benzofuran-5-yl)-1,3,4-oxadiazole decreases tau phosphorylation and ameliorates cognitive deficits in a transgenic model of Alzheimer's disease
A novel glycogen synthase kinase-3 inhibitor 2-methyl-5-(3-{4-[(S)-methylsulfinyl]phenyl}-1-benzofuran-5-yl)-1,3,4-oxadiazole decreases tau phosphorylation and ameliorates cognitive deficits in a transgenic model of Alzheimer's disease
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DOI：
10.1111/j.1471-4159.2011.07532.x
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发表时间：
2011-12-01
影响因子：
4.7
通讯作者：
Takizawa, Masayuki
中科院分区：
文献类型：
--
作者：
Onishi, Tomohiro;Iwashita, Hiroki;Takizawa, Masayuki
阿尔茨海默病(AD)是一种神经退行性疾病，导致认知功能的进行性丧失，病理特征是老年斑和神经原纤维缠结。糖原合成酶-3(GSK-3)参与了AD的发病过程。据报道，GSK-3不仅可以磷酸化tau，这是神经纤维缠结的主要成分，还可以调节沉积在老年斑中的淀粉样β蛋白的产生。因此，药物抑制GSK-3被认为是一种有吸引力的治疗方法。在这项研究中，我们报告了一种新的葛兰素史克-3抑制剂2-methyl-5-(3-{4-[(S)-methylsulfinyl]phenyl}-1-benzofuran-5-yl)-1，3，4-oxadiazole的药理作用，它对葛兰素史克-3具有高选择性，口服后可促进脑组织渗透。MMBO可抑制原代培养神经细胞和正常小鼠脑内tau蛋白的磷酸化。在AD转基因小鼠模型中，MMBO显著降低了海马区GSK-3位点tau的磷酸化水平。此外，慢性给予MMBO抑制了AT8免疫反应评估的tau病理，而不影响淀粉样β病变。最后，在行为评估中，MMBO显著改善了Y迷宫中的记忆和认知缺陷，以及在转基因AD小鼠模型中的新对象识别测试。这些结果表明，药物抑制GSK-3可通过抑制tau磷酸化来改善AD模型小鼠的行为功能障碍，而MMBO可能有利于AD的治疗。
Alzheimers disease (AD) is a neurodegenerative disorder leading to a progressive loss of cognitive function and is pathologically characterized by senile plaques and neurofibrillary tangles. Glycogen synthase kinase-3 (GSK-3) is involved in AD pathogenesis. GSK-3 is reported not only to phosphorylate tau, a major component of neurofibrillary tangles, but also to regulate the production of amyloid beta, which is deposited in senile plaques. Therefore, pharmacological inhibition of GSK-3 is considered an attractive therapeutic approach. In this study, we report the pharmacological effects of a novel GSK-3 inhibitor, 2-methyl-5-(3-{4-[(S)-methylsulfinyl]phenyl}-1-benzofuran-5-yl)-1,3,4-oxadiazole (MMBO), which displays high selectivity for GSK-3 and brain penetration following oral administration. MMBO inhibited tau phosphorylation in primary neural cell culture and also in normal mouse brain. When administered to a transgenic mouse model of AD, MMBO significantly decreased hippocampal tau phosphorylation at GSK-3 sites. Additionally, chronic MMBO administration suppressed tau pathology as assessed by AT8-immunoreactivity without affecting amyloid beta pathology. Finally, in behavioral assessments, MMBO significantly improved memory and cognitive deficits in the Y-maze and in novel object recognition tests in the transgenic AD mouse model. These results indicate that pharmacological GSK-3 inhibition ameliorates behavioral dysfunction with suppression of tau phosphorylation in an AD mouse model, and that MMBO might be beneficial for AD treatment.