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[P1–161]: A PILOT STUDY IN XINJIANG POPULATION IDENTIFIED SIGNIFICANT ASSOCIATIONS OF MAPT RS242557 AND PLAU PROMOTER METHYLATION WITH AD
Author(s) -
Zou Ting,
Zhou Xiaohui,
Wei Chen
Publication year - 2017
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2017.06.228
Subject(s) - methylation , dna methylation , promoter , genotype , gene , genotyping , population , biology , microbiology and biotechnology , medicine , genetics , gene expression , environmental health
we knocked down PPARg expression and measured the effect on mRNA expression. To complement the PPARg knockdown findings we also examined the effects of low doses of PPARg agonists and antagonists (nM range) on mRNA expression of these genes. Results:We discovered PPARg knockdown increased the levels of TOMM40-, APOE-, and APOC1-mRNAs, with the highest increase in expression observed for APOE-mRNA. We also have investigated the effect of PPARg knockdown on cellular functions relevant to Alzheimer’s including cell viability, mitochondria function, cholesterol levels, and ApoE in the media. Using pharmacological approach, we found that low (nM) concentrations of the PPARg agonist Pioglitazone (Pio) decreased transcription of TOMM40, APOE and APOC1 genes, with the lowest mRNA levels for each gene observed at 1.5 nM. Similar to the effect of PPARg knockdown, the strongest response to Pioglitazone was also observed for APOE-mRNA, and another PPARg agonist, Rosiglitazone (Rosi), produced results that were consistent with these. Supporting these findings, treatment with the PPARg antagonist GW9662 led to increased TOMM40, APOE-mRNAs levels at 3nM. Conclusions:our results further established a role for PPARg in regional transcriptional regulation of chr19q13.32, underpinning the association between PPARg, the chr19q13.32 genes cluster, and human complex traits and disease including Alzheimer’s. The importance of our findings is enhanced in the context of the TOMMORROW study, a Phase III trial to evaluate pioglitazone on delay of onset of mild cognitive impairment (MCI), based on a genetics risk algorithm developed using the TOMM40 poly-Tand APOE genotypes and age.