title: gamma-Secretase is differentially modulated by alterations of homocysteine cycle in neuroblastoma and glioblastoma cells.
abstract: 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.
authors.affiliation: Department of Surgery P. Valdoni, University of Rome La Sapienza, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Fuso
authors.forename: Rosaria A
authors.initials: RA
authors.lastname: Cavallaro
authors.forename: Alessandro
authors.initials: A
authors.lastname: Zampelli
authors.forename: Fabrizio
authors.initials: F
authors.lastname: D'Anselmi
authors.forename: Paola
authors.initials: P
authors.lastname: Piscopo
authors.forename: Annamaria
authors.initials: A
authors.lastname: Confaloni
authors.forename: Sigfrido
authors.initials: S
authors.lastname: Scarpa
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor / Q000473:pathology; D019175:DNA Methylation / Q000187:drug effects; D017931:DNA Primers / Q000235:genetics; D005492:Folic Acid / Q000008:administration & dosage / Q000494:pharmacology; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology*; D006710:Homocysteine / Q000378:metabolism*; D006801:Humans; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology*; D018384:Oxidative Stress / Q000502:physiology; D016133:Polymerase Chain Reaction; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000008:administration & dosage / Q000494:pharmacology; D015854:Up-Regulation; D014806:Vitamin B 12 Deficiency / Q000378:metabolism; D026681:Vitamin B 6 Deficiency / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D000975:Antioxidants; D017931:DNA Primers; D053764:Presenilin-1; D006710:Homocysteine; D012436:S-Adenosylmethionine; D005492:Folic Acid; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human