Suppression of Autophagy and Activation of Glycogen Synthase Kinase 3beta Facilitate the Aggregate Formation of Tau.
10.4196/kjpp.2011.15.2.107
- Author:
Song In KIM
1
;
Won Ki LEE
;
Sang Soo KANG
;
Sue Young LEE
;
Myeong Ja JEONG
;
Hee Jae LEE
;
Sung Soo KIM
;
Gall V W JOHNSON
;
Wanjoo CHUN
Author Information
1. Department of Pharmacology, College of Medicine, Kangwon National University, Chunchon 200-701, Korea. wchun@kangwon.ac.kr
- Publication Type:Original Article
- Keywords:
Tau;
Autopahgy;
Glycogen synthase kinase 3beta;
Trehalose;
Neurofibrillary tangles
- MeSH:
Adenine;
Alzheimer Disease;
Autophagy;
Glycogen;
Glycogen Synthase;
Glycogen Synthase Kinase 3;
Glycogen Synthase Kinases;
Neurofibrillary Tangles;
Phosphorylation;
Trehalose
- From:The Korean Journal of Physiology and Pharmacology
2011;15(2):107-114
- CountryRepublic of Korea
- Language:English
-
Abstract:
Neurofibrillary tangle (NFT) is a characteristic hallmark of Alzheimer's disease. GSK3beta 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 GSK3beta-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 GSK3beta. 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 GSK3beta in the presence of 3-MA resulted in significantly increased formation of insoluble tau aggregates. These results indicate that GSK3beta-mediated phosphorylation and compromised autophagic activity significantly contribute to tau aggregation.
