Probing the role of PPARγ in the regulation of late-onset Alzheimer's disease-associated genes

Peroxisome proliferator-activated receptor-gamma (PPAR gamma), is a transcription factor that governs pathways, such as lipid metabolism and immune response, that have been implicated in the etiology of LOAD. Previously, we established HepG2-derived cell-lines with stable knockdown of PPAR gamma gene, and showed an increase in mRNA levels of genes mapped in the APOE linkage disequilibrium (LD) region on chromosome 19q13.32, with the greatest effect observed for APOE-mRNA. Here, we extended the analysis using our PPAR gamma knockdown model system and investigated the broader effect on expression changes of genes implicated in LOAD via genome wide association studies (GWAS). We applied the nCounter gene expression assay (NanoString) using a panel of twenty-four LOAD-associated genes inferred by proximity to the top significantly associated SNPs. Two independent PPAR gamma knockdown cell-lines showed changes in mRNA levels of a total of seven genes compared to a control HepG2 cell-line; six of which, ABCA7, APOE, CASS4, CELF1, PTK2B, and ZCWPW1, were upregulated and one, DSG2, was downregulated upon PPAR gamma knockdown. Our results propose that PPAR gamma may act as a master regulator of the transcription of several genes involved in LOAD pathogenesis. Our study provided the premise for further analyses including a larger set of genes positioned within a wider range of linkage disequilibrium (LD) regions tagged by all LOAD significantly associated SNPs.