Affiliations: [a] Department of Neuroscience, MRC Centre for Neurodegeneration Research, King's College London, Institute of Psychiatry, Denmark Hill, London, UK | [b] Department of Psychological Medicine, King's College London, Institute of Psychiatry, Denmark Hill, London, UK | [c] Discovery Technology Group, Molecular Discovery Research, GlaxoSmithKline, New Frontiers Science Park, Harlow Essex, CM19 5AW, UK | [d] Neurosciences CEDD, GlaxoSmithKline, New Frontiers Science Park, Harlow Essex, CM19 5AW, UK
Correspondence:
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Corresponding author: Jill Richardson, Neurosciences CEDD, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow Essex, CM19 5AW, United Kingdom. E-mail: [email protected].
Abstract: In a recent clinical study, the thiazolidinedione (TZD) pioglitazone (Actos™ 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-γ (PPARγ), 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 PPARγ 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 PPARγ antagonist GW9662 did not significantly reduce these effects, suggesting a PPARγ-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.
