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Current Alzheimer Research

Editor-in-Chief

ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Effect of PSEN1 mutations on MAPT methylation in early-onset Alzheimer’s disease

Author(s): Kirsten G. Coupland, Woojin S. Kim, Glenda M. Halliday, Marianne Hallupp, Carol Dobson-Stone and John B.J. Kwok

Volume 12 , Issue 8 , 2015

Page: [745 - 751] Pages: 7

DOI: 10.2174/1567205012666150710110756

Price: $65

Abstract

The MAPT gene is a risk locus for multiple neurodegenerative diseases, including idiopathic Parkinson’s and Alzheimer’s disease. We examined whether altered DNA methylation of the MAPT promoter, with its potential to modulate gene expression, was a common phenomenon in Alzheimer’s disease patients with differing aetiologies. We measured MAPT promoter methylation in a brain tissue cohort of early-onset Alzheimer’s disease (EOAD) with defined causative mutations in the PSEN1 gene (Normal = 10, PSEN1 AD = 10), and idiopathic late-onset Alzheimer’s disease (Normal = 12, LOAD = 12). We found a brain-region-specific decrease in MAPT promoter methylation in PSEN1 AD patients. Overexpression of PSEN1 reduced MAPT promoter activity in an in vitro luciferase study, and led to an increase in methylation of the endogenous MAPT promoter. Overexpression of PSEN1 with a deletion of exon 9 mutation (Δex9) led to a smaller reduction in MAPT promoter activity relative to wild-type PSEN1 in the luciferase assay, consistent with a decreased ability to modulate endogenous MAPT gene methylation. Our study indicates a novel effect of PSEN1 on MAPT methylation, and suggests a mutation-specific effect of the PSEN1 Δex9 mutation.

Keywords: Alzheimer’s disease, DNA methylation, gene expression, MAPT, mutation, PSEN1.


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