Troglitazone, a peroxisome proliferator-activated receptor-gamma agonist, decreases tau phosphorylation in CHOtau4R cells.
Peroxisome proliferator-activated receptor-gamma (PPARgamma), a member of the nuclear receptor superfamily, is activated by several compounds including the thiazolidinediones. In addition to being a target for diabetes, PPARgamma activation state has recently been shown to modulate beta-amyloid peptide (Abeta) production in cellular models relevant to Alzheimer's disease. Here, we report the effect of troglitazone, a thiazolidinedione, in cells expressing 4-repeat tau. A 24 h treatment with troglitazone significantly reduced phosphorylation of tau at Ser202 and Ser396/404, residues of early and later stages of neurofibrillary tangle accumulation in Alzheimer's disease and other neurodegenerative disorders. Under the same experimental conditions the level of tau did not change. In our cellular model, troglitazone appeared to enhance 3'-phosphoinositide-dependent protein kinase 1 (PDK1) nuclear translocation, resulting in a decrease in cytosolic phosphorylated 70 kDa ribosomal protein kinase (p70S6) and phosphorylated mammalian target of rapamycin (mTor). Furthermore, PPARgamma transcriptional activity did not appear to be responsible for decreased phosphorylation of tau. Thus, we believe that the thiazolidinedione regulates tau phosphorylation through a PPARgamma-dependent/independent mechanism involving an Akt/glycogen synthase kinase-3(GSK-3beta)-independent signalling cascade: PDK1/p70S6K/mTor.
d'Abramo
Cristina
C
Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Ricciarelli
Roberta
R
Pronzato
Maria A
MA
Davies
Peter
P
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology*; D006224:Cricetinae; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D003864:Depression, Chemical; D004797:Enzyme-Linked Immunosorbent Assay; D016874:Neurofibrillary Tangles / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists*; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D045162:Thiazolidinediones / Q000494:pharmacology*; D014162:Transfection; D000077288:Troglitazone; D016875:tau Proteins / Q000378:metabolism*
D002839:Chromans; D047495:PPAR gamma; D045162:Thiazolidinediones; D016875:tau Proteins; D011494:Protein Kinases; D064413:3-Phosphoinositide-Dependent Protein Kinases; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D000077288:Troglitazone