Date Published:

Abstract:

The Presenilin1 (PSEN1) gene encodes the catalytic peptide of the gamma-secretase complex, a key enzyme that cleaves the amyloid-beta protein precursor (A beta PP), to generate the amyloid-beta (A beta) peptides, involved in Alzheimer's Disease (AD). Other substrates of the gamma-secretase, such as E-cadherin and Notch1, are involved in neurodevelopment and haematopoiesis. Gene-specific DNA methylation influences PSEN1 expression in AD animal models. Here we evaluated canonical and non-canonical cytosine methylation patterns of the PSEN1 5MODIFIER LETTER PRIME-flanking during brain development and AD progression, in DNA extracted from the frontal cortex of AD transgenic mice (TgCRND8) and post-mortem human brain. Mapping CpG and non-CpG methylation revealed different methylation profiles in mice and humans. PSEN1 expression only correlated with DNA methylation in adult female mice. However, in post-mortem human brain, lower methylation, both at CpG and non-CpG sites, correlated closely with higher PSEN1 expression during brain development and in disease progression. PSEN1 methylation in blood DNA was significantly lower in AD patients than in controls. The present study is the first to demonstrate a temporal correlation between dynamic changes in PSEN1 CpG and non-CpG methylation patterns and mRNA expression during neurodevelopment and AD neurodegeneration. These observations were made possible by the use of an improved bisulphite methylation assay employing primers that are not biased towards non-CpG methylation. Our findings deepen the understanding of gamma-secretase regulation and support the hypothesis that epigenetic changes can promote the pathophysiology of AD. Moreover, they suggest that PSEN1 DNA methylation in peripheral blood may provide a biomarker for AD.