Fisetin stimulates autophagic degradation of phosphorylated tau via the activation of TFEB and Nrf2 transcription factors.
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-3β-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.
Division of Brain Diseases, Center for Biomedical Sciences, Cheongju-si, Chungcheongbuk-do 363-951, Korea.
Sunhyo
S
Kim
Division of Biosafety Evaluation and Control, Korea National Institute of Health, 187 Osongsaengmyeong2(i)-ro, Osong-eup, Cheongju-si, Chungcheongbuk-do 363-951, Korea.
Ki Ju
KJ
Choi
Division of Brain Diseases, Center for Biomedical Sciences, Cheongju-si, Chungcheongbuk-do 363-951, Korea.
Sun-Jung
SJ
Cho
Division of Brain Diseases, Center for Biomedical Sciences, Cheongju-si, Chungcheongbuk-do 363-951, Korea.
Sang-Moon
SM
Yun
Division of Brain Diseases, Center for Biomedical Sciences, Cheongju-si, Chungcheongbuk-do 363-951, Korea.
Jae-Pil
JP
Jeon
Division of Brain Diseases, Center for Biomedical Sciences, Cheongju-si, Chungcheongbuk-do 363-951, Korea.
Young Ho
YH
Koh
Division of Brain Diseases, Center for Biomedical Sciences, Cheongju-si, Chungcheongbuk-do 363-951, Korea.
Jihyun
J
Song
Department of Anesthesiology, University of Rochester Medical Center, University of Rochester, 601 Elmwood Ave., Rochester, NY 14642, USA.
Gail V W
GV
Johnson
Division of Brain Diseases, Center for Biomedical Sciences, Cheongju-si, Chungcheongbuk-do 363-951, Korea.
Chulman
C
Jo
D000818:Animals; D051381:Rats; D000544:Alzheimer Disease / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D018929:Cell Culture Techniques; D005419:Flavonoids / Q000494:pharmacology; D044948:Flavonols; D047908:Intracellular Signaling Peptides and Proteins; D009474:Neurons / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; C017875:fisetin; D005419:Flavonoids; D044948:Flavonols; D047908:Intracellular Signaling Peptides and Proteins; D051267:NF-E2-Related Factor 2; D010750:Phosphoproteins; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D016875:tau Proteins; C064972:TFEB protein, human