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, John B.J. Kwok.

Journal Name: Current Alzheimer Research

Volume 12 , Issue 8 , 2015

  Journal Home
Translate in Chinese
">

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.

Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 12
ISSUE: 8
Year: 2015
Page: [745 - 751]
Pages: 7
DOI: 10.2174/1567205012666150710110756
Price: $58

Article Metrics

PDF: 24