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김송인,이원기,강상수,Sue-Young Lee,Myeong-Ja Jeong,이희제,김성수,Gall V. W. Johnson,전완주 대한약리학회 2011 The Korean Journal of Physiology & Pharmacology Vol.15 No.2
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.
Kim, Song-In,Lee, Won-Ki,Kang, Sang-Soo,Lee, Sue-Young,Jeong, Myeong-Ja,Lee, Hee-Jae,Kim, Sung-Soo,Johnson, Gall V.W.,Chun, Wan-Joo The Korean Society of Pharmacology 2011 The Korean Journal of Physiology & Pharmacology Vol.15 No.2
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 GSK3${\beta}$-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 GSK3${\beta}$. 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 GSK3${\beta}$ in the presence of 3-MA resulted in significantly increased formation of insoluble tau aggregates. These results indicate that GSK3${\beta}$-mediated phosphorylation and compromised autophagic activity significantly contribute to tau aggregation.