Troglitazone, a peroxisome proliferator-activated receptor-γ agonist, decreases tau phosphorylation in CHOtau4R cells

被引:39
作者
d'Abramo, Cristina
Ricciarelli, Roberta
Pronzato, Maria A.
Davies, Peter
机构
[1] Yeshiva Univ Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10461 USA
[2] Univ Genoa, Dept Expt Med, Genoa, Italy
关键词
dephosphorylation; mammalian target of rapamycin; ribosomal protein kinase; phosphoinositide-dependent protein kinase 1; tau; troglitazone;
D O I
10.1111/j.1471-4159.2006.03931.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Peroxisome proliferator-activated receptor-gamma (PPAR gamma), a member of the nuclear receptor superfamily, is activated by several compounds including the thiazolidinediones. In addition to being a target for diabetes, PPAR gamma activation state has recently been shown to modulate beta-amyloid peptide (A beta) 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, PPAR gamma transcriptional activity did not appear to be responsible for decreased phosphorylation of tau. Thus, we believe that the thiazolidinedione regulates tau phosphorylation through a PPAR gamma-dependent/independent mechanism involving an Akt/glycogen synthase kinase-3(GSK-3 beta)-independent signalling cascade: PDK1/p70S6K/mTor.
引用
收藏
页码:1068 / 1077
页数:10
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