gamma-Secretase is differentially modulated by alterations of homocysteine cycle in neuroblastoma and glioblastoma cells.

Department of Surgery P. Valdoni, University of Rome La Sapienza, Rome, Italy.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 07/2007; 11(3):275-90.
Source: PubMed


Multiple aspects of homocysteine metabolism were studied to understand the mechanism responsible for hyperhomocysteinemia toxicity in Alzheimer disease. Besides oxidative stress and vascular damage, homocysteine has also a great importance in regulating DNA methylation through S-adenosylmethionine, the main methyl donor in eukaryotes. Alterations of S-adenosylmethionine and methylation were evidenced in Alzheimer disease and in elderly. In order to clarify whether DNA methylation can provide the basis for amyloid-beta overproduction, we used human SK-N-BE neuroblastoma and A172 glioblastoma cell lines. We tested the effects of folate, B12 and B6 deprivation and S-adenosylmethionine addition on methylation metabolism. Our results indicate that homocysteine accumulation induced through vitamin B deprivation could impair the "Methylation Potential" with consequent presenilin 1, BACE and amyloid-beta upregulation. Moreover, we found that homocysteine alterations had an effect on neuroblastoma but not on glioblastoma cells; this suggests a possible differential role of the two cell types in Alzheimer disease.

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    • "These compounds interact with glutamate receptors thus increasing intracellular free radicals (Fuso and Scarpa, 2011). Following this trail, a series of studies demonstrated PS1 gene promoter hypomethylation in cell and mouse models under alterative HCY case (Scarpa et al., 2003; Fuso et al., 2005, 2007, 2008). These cases are often accomplished by deficiency of vitamin B6, vitamin B12 and folate during cell culture and mouse feeding. "
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    ABSTRACT: Epigenetic alterations represent a sort of functional modifications related to the genome that are not responsible for changes in the nucleotide sequence. DNA methylation is one of such epigenetic modifications that have been studied intensively for the past several decades. The transfer of a methyl group to the 5 position of a cytosine is the key feature of DNA methylation. A simple change as such can be caused by a variety of factors, which can be the cause of many serious diseases including several neurodegenerative diseases. In this review, we have reviewed and summarized recent progress regarding DNA methylation in four major neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). The studies of these four major neurodegenerative diseases conclude the strong suggestion of the important role DNA methylation plays in these diseases. However, each of these diseases has not yet been understood completely as details in some areas remain unclear, and will be investigated in future studies. We hope this review can provide new insights into the understanding of neurodegenerative diseases from the epigenetic perspective.
    Frontiers in Aging Neuroscience 12/2013; 5:85. DOI:10.3389/fnagi.2013.00085 · 4.00 Impact Factor
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    • "B vitamin deficiency increased SAH levels and PSEN1 and BACE1 upregulation with earlier Aβ plaque deposition [38]. We also showed that SAM administration in vitro can regulate PSEN1 and BACE1 expression and Aβ production [36] [37]. Here we studied SAM supplementation effect on oxidative metabolism in diet-induced hyperhomocysteinemia in TgCRND8 mice by analyzing plasma Hcy, GSH, and its effector enzymes activities (GR, GPx, GST), GSHr/GSSG ratio, and SOD activity in brain, and LPO in erythrocytes. "
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    ABSTRACT: Oxidative stress, altered glutathione levels, and hyperhomocysteinemia play critical roles in Alzheimer's disease. We studied the relationships between hyperhomocysteinemia, glutathione, and oxidative stress in TgCRND8 mice maintained in conditions of folate, B12, and B6 deficiency and the effect of S-adenosylmethionine supplementation. We found that hyperhomocysteinemia was correlated with increased reduced/oxidized brain glutathione ratio, with decreased glutathione S-transferase activity and increased lipid peroxidation. S-adenosylmethionine potentiated superoxide dismutase and glutathione S-transferase activity and restored altered brain glutathione and erythrocytes lipid peroxidation. These results underline the importance of S-adenosylmethionine as neuroprotective compound, acting both on methylation and oxidation metabolism.
    Journal of Alzheimer's disease: JAD 04/2010; 20(4):997-1002. DOI:10.3233/JAD-2010-091666 · 4.15 Impact Factor
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    • "Folate deficiency induces a deleterious cascade of events relevant to AD. The decline in SAM that accompanies folate deficiency promotes overexpression of PS-1, due to impaired DNA methylation, leading to increased activity of BACE and production of Abeta (Fuso et al., 2005, 2007; Scarpa et al., 2003). B vitamin deprivation, which also resulted in decreased SAM, had similar effects (Fuso et al., 2008). "
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    ABSTRACT: Apolipoprotein E4 (ApoE4) is a risk factor for Alzheimer's disease (AD). Whether this risk arises from a deficient function of E4 or the lack of protection provided by E2 or E3 is unclear. Previous studies demonstrate that deprivation of folate and vitamin E, coupled with dietary iron as a pro-oxidant, for 1 month displayed increased presenilin 1 (PS-1) expression, gamma-secretase, and Abeta generation in mice lacking ApoE (ApoE-/- mice). While ApoE-/- mice are a model for ApoE deficiency, they may not reflect the entire range of consequences of E4 expression. We therefore compared herein the impact of the above deficient diet on mice expressing human E2, E3, or E4. As folate deficiency is accompanied by a decrease in the major methyl donor, S-adenosyl methionine (SAM), additional mice received the deficient diet plus SAM. E2 was more protective than murine ApoE or E3 and E4. Surprisingly, PS-1 and gamma-secretase were over-expressed in E3 to the same extent as in E4 even under a complete diet, and were not alleviated by SAM supplementation. Abeta increased only in E4 mice maintained under the complete diet, and was alleviated by SAM supplementation. These findings suggest dietary compromise can potentiate latent risk factors for AD.
    Journal of Neurochemistry 06/2009; 110(3):831-6. DOI:10.1111/j.1471-4159.2009.06177.x · 4.28 Impact Factor
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