title: Suppression of autophagy and activation of glycogen synthase kinase 3beta facilitate the aggregate formation of tau.
abstract: Neurofibrillary tangle (NFT) is a characteristic hallmark of Alzheimer's disease. GSK3β has been reported to play a major role in the NFT formation of tau. Dysfunction of autophagy might facilitate the aggregate formation of tau. The present study examined the role of GSK3β-mediated phosphorylation of tau species on their autophagic degradation. We transfected wild type tau (T4), caspase-3-cleaved tau at Asp421 (T4C3), or pseudophosphorylated tau at Ser396/Ser404 (T4-2EC) in the presence of active or enzyme-inactive GSK3β. Trehalose and 3-methyladenine (3-MA) were used to enhance or inhibit autophagic activity, respectively. All tau species showed increased accumulation with 3-MA treatment whereas reduced with trehalose, indicating that tau undergoes autophagic degradation. However, T4C3 and T4-2EC showed abundant formation of oligomers than T4. Active GSK3β in the presence of 3-MA resulted in significantly increased formation of insoluble tau aggregates. These results indicate that GSK3β-mediated phosphorylation and compromised autophagic activity significantly contribute to tau aggregation.
authors.affiliation: Department of Pharmacology, College of Medicine, Kangwon National University, Chunchon 200-701, Korea.
authors.forename: Song-In
authors.initials: SI
authors.lastname: Kim
authors.forename: Won-Ki
authors.initials: WK
authors.lastname: Lee
authors.forename: Sang-Soo
authors.initials: SS
authors.lastname: Kang
authors.forename: Sue-Young
authors.initials: SY
authors.lastname: Lee
authors.forename: Myeong-Ja
authors.initials: MJ
authors.lastname: Jeong
authors.forename: Hee Jae
authors.initials: HJ
authors.lastname: Lee
authors.forename: Sung-Soo
authors.initials: SS
authors.lastname: Kim
authors.forename: Gall V W
authors.initials: GV
authors.lastname: Johnson
authors.forename: Wanjoo
authors.initials: W
authors.lastname: Chun