The Thiazolidinedione Pioglitazone Increases Cholesterol Biosynthetic Gene Expression in Primary Cortical Neurons by a PPAR gamma-Independent Mechanism

In a recent clinical study, the thiazolidinedione (TZD) pioglitazone (Actos(TM)) was reported to preserve cognitive function in patients with mild to moderate Alzheimer's disease and type II diabetes mellitus. TZDs are agonists of the nuclear hormone receptor peroxisome proliferator-activated receptor-gamma (PPAR gamma), are peripheral insulin sensitizers, and have recently been reported to increase mitochondrial biogenesis in the central nervous system and dendritic spine density. We report a transcriptional profile of the TZD pioglitazone and the non-TZD PPAR gamma agonist GW347845 in primary cortical culture. We observed that pioglitazone, but not GW347845, increased cholesterol biosynthetic and lipogenic gene expression after 6 h, and the expression of the cholesterol efflux transporters Abca1 and Abcg1 after 24 h. Co-treatment of pioglitazone with the PPAR gamma antagonist GW9662 did not significantly reduce these effects, suggesting a PPAR gamma-independent mechanism. These findings suggest a novel effect of TZDs in neurons that may be of relevance as a novel approach against Alzheimer's disease.