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PSEN1 promoter demethylation in hyperhomocysteinemic TgCRND8 mice is the culprit, not the consequence.
No full textIn recent years, in parallel with the growing awareness of the multifactorial nature of Late Onset Alzheimer's Disease, the possibility that epigenetic mechanisms could be involved in the onset and/or progression of the pathology assumed an increasingly intriguing and leading role in Alzheimer's research. Today, many scientific reports indicate the existence of an epigenetic drift during ageing, in particular in Alzheimer's subjects. At the same time, experimental evidences are provided with the aim to demonstrate the causative or consequential role of epigenetic mechanisms. Our research group was involved in the last ten years in studying DNA methylation, the main epigenetic modification, in relationship to altered one-carbon metabolism (namely high homocysteine and low B vitamins levels), in Alzheimer's experimental models. Our previous findings about the demethylation of Presenilin1 gene promoter in nutritionally-induced hyperhomocysteinemia in a transgenic mouse model clearly demonstrated that Presenilin1 is regulated by DNA methylation. One of the open questions raised by our studies was if the observed demethylation was solely due to the induced imbalance of one-carbon metabolism or could be a response to the massive deposition of amyloid plaques in transgenic mice. Here we analyzed old (10 months) mice under standard diet in order to evidence possible changes in Presenilin1 promoter methylation in transgenic (TgCRND8 mice, carrying a double-mutated human APP transgene) vs. wt mice (129Sv) after prolonged exposure to amyloid. We found no differences in Presenilin1 methylation despite a slight increase in gene expression; these results suggest that amyloid production is not responsible for Presenilin1 demethylation in TgCRND8 mice brain
DNA methylase and demethylase activities are modulated by one-carbon metabolism in Alzheimer's disease models
No full textLate-onset Alzheimer's disease seems to be a multi-factorial disease with both genetic and non-genetic, environmental, possible causes. Recently, epigenomics is achieving a major role in Alzheimer's research due to its involvement in different molecular pathways leading to neurodegeneration. Among the different epigenetic modifications. DNA methylation is one of the most relevant to the disease. We previously demonstrated that presenilin1 (PSEN1), a gene involved in amyloidogenesis, is modulated by DNA methylation in neuroblastoma cells and Alzheimer's mice in an experimental model of nutritionally altered one-carbon metabolism. This alteration, obtained by nutritional deficiency of B vitamins (folate, B12 and B6) hampered S-adenosylmethionine (SAM)-dependent methylation reactions. The aim of the present paper was to investigate the regulation of DNA methylation machinery in response to hypomethylating (B vitamin deficiency) and hypermethylating (SAM supplementation) alterations of the one-carbon metabolism. We found that DNA methylases (DNMT1, 3a and 3b) and a putative demethylase (MBD2) were differently modulated, in line with the previously observed changes of PSEN1 methylation pattern in the same experimental conditions. (C) 2011 Elsevier Inc. All rights reserved
Gene silencing through methylation: an epigenetic intervention on Alzheimer Disease
No full textAlzheimer disease (AD) is among the few diseases that may display high homocysteine (HCY) and low B12 and folate in blood. This observation has raised the suspect that amyloid-β overproduction and accumulation, which may be the cause of the disease, could be due to the loss of epigenetic control in the expression of the genes involved in AβPP (amyloid-β protein precursor) processing. We have shown, in cell culture, that two of the genes responsible for amyloid-β production are controlled by the methylation of their promoters. The process is strictly related to S-adenosylmethionine (SAM) metabolism. SAM is a natural compound, mainly produced by the liver, which has been found at very low concentrations in AD brains. A further support to this thesis came from the observation that in elderly DNA methylations are consistently lower than in young and mid aged people. We are actually experimenting in transgenic mice the possibility to prevent or to arrest amyloid-β accumulation, through SAM administration, and therefore its significance and the use of this drug for the treatment of the disease. © 2006 - IOS Press and the authors. All rights reserved
Changes in Presenilin 1 gene methylation pattern in diet-induced B vitamin deficiency
No full textWe have previously shown that a nutritional model of B vitamin deficiency and homocysteine cycle alteration could lead to increased amyloid beta deposition, due to PSEN 1 and BACE over-expression and consequent increase in secretase activity. We hypothesize that nutritional factors causing homocysteine cycle alterations (i.e. hyperhomocysteinemia) could induce sequence-specific DNA hypomethylation and "aberrant" gene activation. Aim of present study was to analyze the methylation pattern of PSEN 1 promoter in SK-N-BE neuroblastoma cells and TgCRND8 mice, in a B vitamin (folate, B12 and B6) deficiency paradigm. PSEN 1 methylation status has been evaluated through bisulphite modification and genomic sequencing. We demonstrate that B vitamin deficiency induces hypomethylation of specific CpG moieties in the 5'-flanking region; S-adenosylmethionine has been supplemented as methyl donor to reverse this effect. PSEN 1 promoter methylation status is correlated with gene expression. These findings pinpoint a direct relationship between B vitamin-dependent alteration of homocysteine cycle and DNA methylation and also indicate that PSEN 1 promoter is regulated by methylation of specific CpG moieties. (C) 2009 Elsevier Inc. All rights reserved
Role of S-adenosylmethionine in the modulation of oxidative stress-related neurodegeneration
No full textS-adenosyl-L-methionine (SAM) is the main biological methyl donor in transmethylation reactions,
consisting in the transferring of a methyl moiety to different substrates including DNA, proteins, lipids
and RNA. SAM level in the organism decreases with aging and restoring the original levels through
exogenous supplementation is an important tool for the improvement of many vital functions. Indeed,
SAM deficiency may contribute to the onset of several diseases, i.e. depression, liver diseases, osteoarthritis
and senile neurological disorders such as Alzheimer’s and Parkinson’s diseases. Recent evidences indicate
that SAM may have an involvement in oxidative stress, a process which typically involves an alteration of
cellular sulfur amino acids homeostasis. SAM is not only the principal methyl donor, but also a precursor
of glutathione, the major endogenous antioxidant, whose role in counteracting oxidative stress is well
known. In this review we will highlight the role of SAM not just as a methyl-donor but also as a regulator
of different metabolic pathways involved in the antioxidant response in brain related disorders
The effect of S-adenosylmethionine on CNS gene expression studied by cDNA microarrays analysis
No full textHigh homocysteine (Hcy) together with low S-adenosylmethionine (SAM) levels are often observed in Alzheimer disease (AD), and this could be a sign of alteration of SAM/Hcy metabolism. It has already been shown that DNA methylation is involved in amyloid-β-protein precursor (AβPP) processing and amyloid-β(Aβ) production through the regulation of Presenilin 1 (PS1) expression and that exogenous SAM can silence the gene reducing Aβ. To investigate whether SAM administration globally influenced gene expression in the brain, we analysed 588 genes of the central nervous system in SK-N-BE neuroblastoma cells, with cDNA probes derived from untreated (DM; Differentiation Medium) or SAM treated (DM + SAM) cultures. In these conditions only seven genes were modulated by SAM treatment (and therefore by DNA methylation); three were up-regulated and four down-regulated, showing low levels of modulation. © 2006 - IOS Press and the authors. All rights reserved
Efefct of one-carbon metabolism alteration on DNA methylation machinery in Alzheimer’s Disease models. .
No full text
S-adenosylmethionine reduces the progress of the Alzheimer-like features induced by B-vitamin deficiency in mice
No full textMethylation reactions linked to homocysteine in the one-carbon metabolism are increasingly elicited in Alzheimer's disease, although the association of hyperhomocysteinemia and of low B vitamin levels with the disease is still debated. We previously demonstrated that hyperhomocysteinemia and DNA hypomethylation induced by B vitamin deficiency are associated with PSEN1 and BACE1 overexpression and amyloid production. The present study is aimed at assessing S-adenosylmethionine effects in mice kept under a condition of B vitamin deficiency. To this end, TgCRND8 mice and wild-type littermates were assigned to control or B vitamin deficient diet, with or without S-adenosylmethionine supplementation. We found that S-adenosylmethionine reduced amyloid production, increased spatial memory in TgCRND8 mice and inhibited the upregulation of B vitamin deficiency-induced PSEN1 and BACE1 expression and Tau phosphorylation in TgCRND8 and wild-type mice. Furthermore, S-adenosylmethionine treatment reduced plaque spreading independently on B vitamin deficiency. These results strengthen our previous observations on the possible role of one-carbon metabolism in Alzheimer's disease, highlighting hyperhomocysteinemia-related mechanisms in dementia onset/progression and encourage further studies aimed at evaluating the use of S-adenosylmethionine as a potential candidate drug for the treatment of the disease. (C) 2012 Elsevier Inc. All rights reserved
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