gamma-Secretase is differentially modulated by alterations of homocysteine cycle in neuroblastoma and glioblastoma cells.
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.
Fuso
Andrea
A
Department of Surgery P. Valdoni, University of Rome La Sapienza, Rome, Italy.
Cavallaro
Rosaria A
RA
Zampelli
Alessandro
A
D'Anselmi
Fabrizio
F
Piscopo
Paola
P
Confaloni
Annamaria
A
Scarpa
Sigfrido
S
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
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