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.