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

J. Neurochem. (2011) 10.1111/j.1471‐4159.2011.07532.x Alzheimer’s 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 β, 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 β 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. A novel glycogen synthase kinase‐3 inhibitor MMBO shows therapeutic effects in AD mouse model. Glycogen synthase kinase‐3 (GSK‐3) is involved in AD pathogenesis as one of tau kinases. We report that a novel selective GSK‐3 inhibitor MMBO lowers tau phosphorylation in vitro and in vivo, and ameliorates AD‐like symptoms in AD mouse model. These results indicate that MMBO and the resultant decrease in tau phosphorylation may represent a valid therapeutic strategy for AD.