title: 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.
abstract: 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.
authors: Pharmacology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited, Juso-Honmachi, Yodogawa, Osaka, Japan. Oonishi_Tomohiro@takeda.co.jp
authors: Tomohiro
authors: T
authors: Onishi
authors: Hiroki
authors: H
authors: Iwashita
authors: Yumiko
authors: Y
authors: Uno
authors: Jun
authors: J
authors: Kunitomo
authors: Morihisa
authors: M
authors: Saitoh
authors: Eiji
authors: E
authors: Kimura
authors: Hisashi
authors: H
authors: Fujita
authors: Noriko
authors: N
authors: Uchiyama
authors: Masakuni
authors: M
authors: Kori
authors: Masayuki
authors: M
authors: Takizawa
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D018929:Cell Culture Techniques; D002540:Cerebral Cortex / Q000166:cytology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D005106:Exploratory Behavior / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects; D010069:Oxadiazoles / Q000494:pharmacology / Q000627:therapeutic use; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D053764:Presenilin-1 / Q000235:genetics; D013997:Time Factors; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C569487:2-methyl-5-(3-(4-(methylsulfinyl)phenyl)-1-benzofuran-5-yl)-1,3,4-oxadiazole; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001572:Benzofurans; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha