S-adenosylmethionine and superoxide dismutase 1 synergistically counteract Alzheimer's disease features progression in tgCRND8 mice

Recent evidence emphasizes the role of dysregulated one-carbon metabolism in Alzheimer's Disease (AD). Exploiting a nutritional B-vitamin deficiency paradigm, we have previously shown that PSEN1 and BACE1 activity is modulated by one-carbon metabolism, leading to increased amyloid production. We have also demonstrated that S-adenosylmethionine (SAM) supplementation contrasted the AD-like features, induced by B-vitamin deficiency. In the present study, we expanded these observations by investigating the effects of SAM and SOD (Superoxide dismutase) association. TgCRND8 AD mice were fed either with a control or B-vitamin deficient diet, with or without oral supplementation of SAM + SOD. We measured oxidative stress by lipid peroxidation assay, PSEN1 and BACE1 expression by Real-Time Polymerase Chain Reaction (PCR), amyloid deposition by ELISA assays and immunohistochemistry. We found that SAM + SOD supplementation prevents the exacerbation of AD-like features induced by B vitamin deficiency, showing synergistic effects compared to either SAM or SOD alone. SAM + SOD supplementation also contrasts the amyloid deposition typically observed in TgCRND8 mice. Although the mechanisms underlying the beneficial effect of exogenous SOD remain to be elucidated, our findings identify that the combination of SAM + SOD could be carefully considered as co-adjuvant of current AD therapies

P4‐181: Homocysteine, S‐adenosylmethionine/s‐adenosylhomocysteine ratio, glutathione and nitric oxide levels in TgCRDND8 mice fed with B vitamin‐deficient diet

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Changes in Myosin and Myosin Light Chain Kinase During Myogenesis

Myosins and myosin light chain kinases have been isolated from a cloned line of myoblasts (L5/A10) as this cell line undergoes differentiation toward adult muscle. At least three myosin isozymes were obtained during this developmental process. Initially a nonmuscle type of myosin was found in the myoblasts. The molecular weights of the myoblast light chains were 20 000 and 15 000. Myosin isolated from early myotubes had light chains with molecular weights of 20 000 and 19 500. Myosin isolated from myotubes which contained sarcomeres had light chains with molecular weights of 23 000, 18 500, and 16000. This last myosin was similar in light chain complement to adult rat thigh muscle. Two forms of the myosin light chain kinase activity were detected: a calciumindependent kinase in the myoblasts and a calcium-dependent kinase in the myotubes with sarcomeres. No myosin light chain kinase activity was detected in the early myotubes

Changes in Myosin and Myosin Light Chain Kinase During Myogenesis

Myosins and myosin light chain kinases have been isolated from a cloned line of myoblasts (L5/A10) as this cell line undergoes differentiation toward adult muscle. At least three myosin isozymes were obtained during this developmental process. Initially a nonmuscle type of myosin was found in the myoblasts. The molecular weights of the myoblast light chains were 20 000 and 15 000. Myosin isolated from early myotubes had light chains with molecular weights of 20 000 and 19 500. Myosin isolated from myotubes which contained sarcomeres had light chains with molecular weights of 23 000, 18 500, and 16000. This last myosin was similar in light chain complement to adult rat thigh muscle. Two forms of the myosin light chain kinase activity were detected: a calciumindependent kinase in the myoblasts and a calcium-dependent kinase in the myotubes with sarcomeres. No myosin light chain kinase activity was detected in the early myotubes

Disclosing bias in bisulfite assay: MethPrimers underestimate high DNA methylation

Discordant results obtained in bisulfite assays using MethPrimers (PCR primers designed using MethPrimer software or assuming that non-CpGs cytosines are non methylated) versus primers insensitive to cytosine methylation lead us to hypothesize a technical bias. We therefore used the two kinds of primers to study different experimental models and methylation statuses. We demonstrated that MethPrimers negatively select hypermethylated DNA sequences in the PCR step of the bisulfite assay, resulting in CpG methylation underestimation and non-CpG methylation masking, failing to evidence differential methylation statuses. We also describe the characteristics of "Methylation-Insensitive Primers" (MIPs), having degenerated bases (G/A) to cope with the uncertain C/U conversion. As CpG and non-CpG DNA methylation patterns are largely variable depending on the species, developmental stage, tissue and cell type, a variable extent of the bias is expected. The more the methylome is methylated, the greater is the extent of the bias, with a prevalent effect of non-CpG methylation. These findings suggest a revision of several DNA methylation patterns so far documented and also point out the necessity of applying unbiased analyses to the increasing number of epigenomic studies

Epigenetics and nutrition: B-vitamin deprivation and its impact on brain amyloid

Epigenetics is becoming the epicentre of modern medicine because it is beginning to clarify the relationship between genetic background, environment, aging, and disease. SAM-dependent DNA methylation at the 5-position of cytosine within CpG dinucleotides represents an important mechanism for epigenetic control of gene expression and maintenance of genome integrity. Hence, methyl deficiency leads to disturbances in gene expression. B vitamins (B12, B6, and folate) have a pivotal role in reducing homocysteine accumulation by remethylation to form methionine and by transsulfuration to form glutathione (GSH). B vitamins have therefore a central function in SAM synthesis, in gene expression, and in the synthesis of one of the major antioxidant molecules. The physiological causes of AD onset are not yet well understood, but it has been shown that changes in DNA methylation due to vitamin deficiency contributes to the basic mechanisms responsible for AD onset. Accordingly, restoration of gene methylation pattern could be a target for preventing AD or arresting the progression of disease. A methyl donor such as SAM can repair the DNA methylation pattern and thereby restore normal biological functions in AD mice. Recent studies indicate that B vitamin deprivation and SAM supplementation, which modify the SAM cycle, can influence amyloidogenesis in mice, probably via SAM-dependent methylation reactions. SAM supplementation has been shown to reduce beta amyloid in mice brain

One-carbon metabolism and Alzheimer's disease: is it all a methylation matter?

The sporadic form of Alzheimer disease, late onset Alzheimer's disease (LOAD), is a multifactorial disease; a strong link between nutritional and genetic factors with normal aging and dementia is supported by studies on nutrition, metabolism, and neurodegeneration. Specifically, the involvement of homocysteine (HCY) and its dietary determinants (vitamins B6, B12, and folate, besides methionine) in dementia has been a topic of intense investigation. In this Commentary we would like to highlight the role of 1-carbon metabolism in epigenetics and Alzheimer's disease and evidence the coinvolvement of this metabolism in amyloid and tau pathways. (C) 2011 Elsevier Inc. All rights reserved