Ornit Chiba-Falek
Duke University Medical Center, Durham, USA
Title: The functional role of an Alzheimer’s disease associated poly-T variant in TOMM40 gene
Biography
Biography: Ornit Chiba-Falek
Abstract
We investigated the TOMM40-APOE genomic region that has been associated with the risk and age of onset of lateonset Alzheimer’s disease (LOAD) and with cognitive function in healthy aging to determine if a highly polymorphic, intronicpoly-T within this region (rs10524523, hereaft er 523) aff ects expression of the APOE and TOMM40 genes. Alleles of this locus are classifi ed: Short-S, long-L, very long-VL based on the number of T-residues. We analyzed two brain regions from Caucasian donors,APOEε3/3 and APOEε3/4autopsy-confi rmed LOAD cases and APOEε3/3 normal controls. Diff erences in APOE-mRNA and TOMM40-mRNA levels were evaluated as a function of 523-genotype. Th e expression of both genes was signifi cantly increased with disease. Mean expression of APOE-and TOMM40-mRNA levels were higher in VL-homozygotes compared to S-homozygotes in temporal and occipital cortexes from Normal and LOAD carriers of APOEε3/3 haplotype. Similarly, among APOEε3/4 LOAD subjects APOE and TOMM40-mRNAs expression were increased in VL-heterozygotes compared to S-heterozygotes brains.We further investigated the eff ect of the 523 locus in its native genomic context using a luciferase reporter system.Th e results were consistent with the human brain mRNA analysis: Th e 523-VL resulted in signifi cantly higher expression than the S in both HepG2 hepatoma and SH-SY5Y neuroblastoma cell-lines. Collectively, these results suggested that the 523 locus may contribute to LOAD susceptibility by modulating the expression of TOMM40 and or APOE transcription.In conclusion, our study elucidated the mechanism of action of TOMM40-523, a genetic risk factor for LOAD and provides functional support for the role of the 523 locus in the pathogenesis of LOAD.