Fisetin stimulates autophagic degradation of phosphorylated tau via theactivation of TFEB and Nrf2 transcription factors

Collection with item attached
2016
Item details URL
http://open-repository.kisti.re.kr/cube/handle/open_repository/479080.do
DOI
10.1038/srep24933
Title
Fisetin stimulates autophagic degradation of phosphorylated tau via theactivation of TFEB and Nrf2 transcription factors
Description
We thank Drs Peter Davies (Albert Einstein College of Medicine), PeterSeubert (Prothena, Inc.) and Eui-ju Choi (Korea University) forproviding materials for this study. This study was supported by a grantof the Ministry of Health and Welfare and Korea National Institute ofHealth Intramural Research Grant (4845-302-210-13).
abstract
The neuronal accumulation of phosphorylated tau plays a critical role in the pathogenesis of Alzheimer's disease (AD). Here, we examined the effect of fisetin, a flavonol, on tau levels. Treatment of cortical cells or primary neurons with fisetin resulted in significant decreases in the levels of phosphorylated tau. In addition, fisetin decreased the levels of sarkosyl-insoluble tau in an active GSK-3 beta-induced tau aggregation model. However, there was no difference in activities of tau kinases and phosphatases such as protein phosphatase 2A, irrespective of fisetin treatment. Fisetin activated autophagy together with the activation of transcription factor EB (TFEB) and Nrf2 transcriptional factors. The activation of autophagy including TFEB is likely due to fisetin-mediated mammalian target of rapamycin complex 1 (mTORC1) inhibition, since the phosphorylation levels of p70S6 kinase and 4E-BP1 were decreased in the presence of fisetin. Indeed, fisetin-induced phosphorylated tau degradation was attenuated by chemical inhibitors of the autophagy-lysosome pathway. Together the results indicate that fisetin reduces levels of phosphorylated tau through the autophagy pathway activated by TFEB and Nrf2. Our result suggests fisetin should be evaluated further as a potential preventive and therapeutic drug candidate for AD.
provenance
Made available in Cube on 2018-09-28T12:50:08Z (GMT). No. of bitstreams: 0
language
English
author
Kim, Sunhyo
Choi, Ki Ju
Cho, Sun-Jung
Yun, Sang-Moon
Jeon, Jae-Pil
Koh, Young Ho
Song, Jihyun
Johnson, Gail V. W.
Jo, Chulman
orcid
di Ronza, Alberto/0000-0002-9813-5143
accessioned
2018-09-28T12:50:08Z
available
2018-09-28T12:50:08Z
issued
2016
citation
SCIENTIFIC REPORTS(6)
issn
2045-2322
uri
http://open-repository.kisti.re.kr/cube/handle/open_repository/479080.do
Funder
보건복지부
Funding Program
만성병관리기술개발연구
Project ID
1465019456
Jurisdiction
Rep.of Korea
Project Name
Study on the role of Nrf2 in Alzheimer's disease pathology
rights
openAccess
type
article


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