title: Morin attenuates tau hyperphosphorylation by inhibiting GSK3β.
abstract: Alzheimer's disease (AD) is the major form of age-related dementia and is characterized by progressive cognitive impairment, the accumulation of extracellular amyloid β-peptide (Aβ), and intracellular hyperphosphorylated tau aggregates in affected brain regions. Tau hyperphosphorylation and accumulation in neurofibrillary tangles is strongly correlated with cognitive deficits, and is apparently a critical event in the dementia process because mutations in tau can cause a tangle-only form of dementia called frontotemporal lobe dementia. Among kinases that phosphorylate tau, glycogen synthase kinase 3β (GSK3β) is strongly implicated in AD pathogenesis. In the present study, we established an ELISA to screen for agents that inhibit GSK3β activity and found that the flavonoid morin effectively inhibited GSK3β activity and blocked GSK3β-induced tau phosphorylation in vitro. In addition, morin attenuated Aβ-induced tau phosphorylation and protected human neuroblastoma cells against Aβ cytotoxicity. Furthermore, treatment of 3xTg-AD mice with morin resulted in reductions in tau hyperphosphorylation and paired helical filament-like immunoreactivity in hippocampal neurons. Morin is a novel inhibitor of GSK3β that can reduce tau pathology in vivo and may have potential as a therapeutic agent in tauopathies.
authors.affiliation: Department of Pharmacy, College of Pharmacy and Research Institute for Drug Development, Longevity Life Science and Technology Institutes, Pusan National University, Geumjeong-gu, Busan, Republic of Korea.
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Gong
authors.forename: Hee Ra
authors.initials: HR
authors.lastname: Park
authors.forename: Mi Eun
authors.initials: ME
authors.lastname: Kim
authors.forename: Shunfu
authors.initials: S
authors.lastname: Piao
authors.forename: Eunjin
authors.initials: E
authors.lastname: Lee
authors.forename: Dong-Gyu
authors.initials: DG
authors.lastname: Jo
authors.forename: Hae Young
authors.initials: HY
authors.lastname: Chung
authors.forename: Nam-Chul
authors.initials: NC
authors.lastname: Ha
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.forename: Jaewon
authors.initials: J
authors.lastname: Lee
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D005419:Flavonoids / Q000494:pharmacology* / Q000627:therapeutic use; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009447:Neuroblastoma / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D016875:tau Proteins / Q000378:metabolism* / Q000633:toxicity; D047309:Flavones
chemical_list: D000975:Antioxidants; D005419:Flavonoids; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D018696:Neuroprotective Agents; D016875:tau Proteins; C008548:morin; D047309:Flavones; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse