title: Troglitazone, a thiazolidinedione, decreases tau phosphorylation through the inhibition of cyclin-dependent kinase 5 activity in SH-SY5Y neuroblastoma cells and primary neurons.
abstract: The peroxisome proliferator-activated receptor gamma(PPARc) agonists thiazolidinediones (TZDs) are prescribed for the treatment of type 2 diabetes mellitus. Furthermore, it has been reported that TZDs have a beneficial effect on neurodegenerative disorders, such as Alzheimer’s disease. However, the molecular mechanisms underlying this effect are not fully understood. Here, we investigated whether and how troglitazone, a parent TZD drug, inhibits tau phosphorylation.Treatment with troglitazone decreased tau-Thr231 phosphorylation and p35, the specific activator of cyclin-dependent kinase 5 (CDK5), in a dose- and time-dependent manner. Troglitazone also decreased CDK5 enzymatic activity, and ectopic expression of p25, the cleaved and more active form of p35, restored the troglitazone-induced decrease in tau-Thr231 phosphorylation. Treatment with either MG-132, a reversible proteasome inhibitor, or lactacystin, a specific and irreversible 26S proteasome inhibitor, significantly reversed the observed inhibitory effects of troglitazone. However, GW9662, a specific and irreversible PPARc antagonist, did not alter the observed inhibitory effects. Similar results were also found when other TZD drugs, pioglitazone and rosiglitazone, were used. Treatment with various inhibitors revealed that troglitazone-induced inhibitions of tau-Thr231 phosphorylation and p35 expression were not mediated by glycogen synthase kinase 3b, protein kinase A, and protein phosphatase 2A signaling pathways.Finally, we also found that the same observed inhibitory effects of troglitazone hold true for the use of primary cortical neurons. Taken together, we demonstrated that TZDs repressed tau-Thr231 phosphorylation via the inhibition of CDK5 activity, which was mediated by the proteasomal degradation of p35 and a PPARc-independent signaling pathway.
authors.affiliation: Department of Neurology, Konkuk University Medical Center, Konkuk University, Seoul, South Korea.
authors.forename: Du-Hyong
authors.initials: DH
authors.lastname: Cho
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Lee
authors.forename: Kyoung Ja
authors.initials: KJ
authors.lastname: Kwon
authors.forename: Chan Young
authors.initials: CY
authors.lastname: Shin
authors.forename: Kee-Ho
authors.initials: KH
authors.lastname: Song
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Park
authors.forename: Inho
authors.initials: I
authors.lastname: Jo
authors.forename: Seol-Heui
authors.initials: SH
authors.lastname: Han
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology*; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D047468:Immunoprecipitation; D009474:Neurons / Q000187:drug effects*; D047495:PPAR gamma / Q000819:agonists*; D010766:Phosphorylation / Q000187:drug effects; D000077205:Pioglitazone; D054648:Protein Phosphatase 2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D014162:Transfection; D000077288:Troglitazone; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D002839:Chromans; D047495:PPAR gamma; D045162:Thiazolidinediones; D016875:tau Proteins; D000077154:Rosiglitazone; D051360:Cyclin-Dependent Kinase 5; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D054648:Protein Phosphatase 2; D000077288:Troglitazone; D000077205:Pioglitazone
keywords: cyclin-dependent kinase 5; p35; phosphorylation; proteasomal degradation; tau; troglitazone