TY - JOUR T1 - 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. AU - Onishi,Tomohiro, AU - Iwashita,Hiroki, AU - Uno,Yumiko, AU - Kunitomo,Jun, AU - Saitoh,Morihisa, AU - Kimura,Eiji, AU - Fujita,Hisashi, AU - Uchiyama,Noriko, AU - Kori,Masakuni, AU - Takizawa,Masayuki, Y1 - 2011/11/02/ PY - 2011/10/14/entrez PY - 2011/10/14/pubmed PY - 2012/1/27/medline SP - 1330 EP - 40 JF - Journal of neurochemistry JO - J Neurochem VL - 119 IS - 6 N2 - 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. SN - 1471-4159 UR - https://www.unboundmedicine.com/medline/citation/21992552/A_novel_glycogen_synthase_kinase_3_inhibitor_2_methyl_5__3_{4_[_S__methylsulfinyl]phenyl}_1_benzofuran_5_yl__134_oxadiazole_decreases_tau_phosphorylation_and_ameliorates_cognitive_deficits_in_a_transgenic_model_of_Alzheimer's_disease_ L2 - https://doi.org/10.1111/j.1471-4159.2011.07532.x DB - PRIME DP - Unbound Medicine ER -