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

Sapienza University of Rome, Roma, Latium, 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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Available from: Andrea Fuso
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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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    • "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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    • "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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