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Troglitazone, a peroxisome proliferator‐activated receptor‐γ agonist, decreases tau phosphorylation in CHOtau4R cells
Author(s) -
D'Abramo Cristina,
Ricciarelli Roberta,
Pronzato Maria A.,
Davies Peter
Publication year - 2006
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.03931.x
Subject(s) - troglitazone , thiazolidinedione , gsk 3 , phosphorylation , protein kinase b , ciglitazone , microbiology and biotechnology , pi3k/akt/mtor pathway , chemistry , peroxisome proliferator activated receptor , kinase , neurodegeneration , receptor , biology , endocrinology , medicine , signal transduction , biochemistry , diabetes mellitus , type 2 diabetes , disease
Peroxisome proliferator‐activated receptor‐γ (PPARγ), a member of the nuclear receptor superfamily, is activated by several compounds including the thiazolidinediones. In addition to being a target for diabetes, PPARγ activation state has recently been shown to modulate β‐amyloid peptide (Aβ) 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, PPARγ transcriptional activity did not appear to be responsible for decreased phosphorylation of tau. Thus, we believe that the thiazolidinedione regulates tau phosphorylation through a PPARγ‐dependent/independent mechanism involving an Akt/glycogen synthase kinase‐3(GSK‐3β)‐independent signalling cascade: PDK1/p70S6K/mTor.