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KMID : 0811720110150020107
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Korean Journal of Physiology & Pharmacology
2011 Volume.15 No. 2 p.107 ~ p.114
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Suppression of Autophagy and Activation of Glycogen Synthase Kinase 3beta Facilitate the Aggregate Formation of Tau
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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
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Abstract
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Neurofibrillary tangle (NFT) is a characteristic hallmark of Alzheimer’s disease. GSK3? 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?-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?. 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? in the presence of 3-MA resulted in significantly increased formation of insoluble tau aggregates. These results indicate that GSK3?-mediated phosphorylation and compromised autophagic activity significantly contribute to tau aggregation.
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KEYWORD
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Tau, Autopahgy, Glycogen synthase kinase 3?, Trehalose, Neurofibrillary tangles
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