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Korean J Physiol Pharmacol. 2011 Apr;15(2):107-14. doi: 10.4196/kjpp.2011.15.2.107. Epub 2011 Apr 30.

Suppression of autophagy and activation of glycogen synthase kinase 3beta facilitate the aggregate formation of tau.

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  • 1Department of Pharmacology, College of Medicine, Kangwon National University, Chunchon 200-701, Korea.

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.

KEYWORDS:

Autopahgy; Glycogen synthase kinase 3β; Neurofibrillary tangles; Tau; Trehalose

PMID:
21660151
PMCID:
PMC3104199
DOI:
10.4196/kjpp.2011.15.2.107
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