CpG and non-CpG Presenilin1 methylation pattern in course of neurodevelopment and neurodegeneration is associated with gene expression in human and murine brain

Abstract

The Presenilin1 (PSEN1) gene encodes the catalytic peptide of the γ-secretase complex, a key enzyme that cleaves the amyloid-β protein precursor (AβPP), to generate the amyloid-β (Aβ) peptides, involved in Alzheimer's Disease (AD). Other substrates of the γ-secretase, such as Ecadherin 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 5ʹ-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 γ-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.

Functional Foods: An Approach to Modulate Molecular Mechanisms of Alzheimer’s Disease

“…Recent research is increasingly shedding light in the biochemical, cellular and epigenetic modifications produced by a series of plant polyphenols, with particular emphasis on the olive ones [331].…”

“…Similarly, RSV, a plant polyphenol which is found in peanuts, mulberries, cranberries and mostly in the skin of grapes, inhibits DNMT activity (but in a lesser extent than EGCG) [358] (Figure 3). In addition, quercetin [331] and EVOO polyphenols were shown to activate the Sirt1 path, with possible relevance for AD prevention/treatment [331]. In addition, caffeic acid, a common catechol-containing coffee polyphenol, present also in barley grain, inhibits DNA methylation [368].…”

“…In addition, the isoflavone GEN, one of the phytoestrogens found in soybeans (see above, Section 4), is able to regulate gene transcription by affecting epigenetic modifications [358] and its effect on epigenetic alterations has been widely investigated in cancer but not in the field of AD. However, GEN has been proved to reduce DNMT activity by forming a complex with it [331].…”

“…Histone modifications can result from the activity of various enzymes, including histone acetyltransferases (HATs), HDACs, histone methyltransferases (HMTs) and histone demethylases (HDMs) [331].…”

“…For example, EGCG, isolated from green tea, acts as a histone modifier, interfering with the HDAC and HAT activities [331]. It also contributes to histone posttranslational modifications by inhibiting histone methyltransferases [383].…”