S-adenosylmethionine/homocysteine cycle alterations modify DNA methylation status with consequent deregulation of PS1 and BACE and beta-amyloid production.
Few diseases are characterized by high homocysteine (HCY) and low folate and vitamin B12 blood levels. Alzheimer disease (AD) is among these. It has already been shown that DNA methylation is involved in amyloid precursor protein (APP) processing and beta-amyloid (A beta) production through the regulation of Presenilin1 (PS1) expression and that exogenous S-adenosylmethionine (SAM) can silence the gene reducing A beta production. Here we demonstrate that BACE (beta-secretase), as well as PS1, is regulated by methylation and that the reduction of folate and vitamin B12 in culture medium can cause a reduction of SAM levels with consequent increase in presenilin1 and BACE levels and with increase in A beta production. The simultaneous administration of SAM to the deficient medium can restore the normal gene expression, thus reducing the A beta levels. The use of deprived medium was intended to mimic a mild nutritional deficit involved in the onset of AD.
Fuso
Andrea
A
Laboratorio di Ricerca, Dipartimento di Chirurgia P. Valdoni, Università di Roma La Sapienza, 00161 Rome, Italy.
Seminara
Laura
L
Cavallaro
Rosaria A
RA
D'Anselmi
Fabrizio
F
Scarpa
Sigfrido
S
D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis; D016282:Aspartic Acid Endopeptidases; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D045744:Cell Line, Tumor; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D019175:DNA Methylation; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D005494:Folic Acid Deficiency / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006710:Homocysteine / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D053764:Presenilin-1; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D012436:S-Adenosylmethionine / Q000378:metabolism* / Q000494:pharmacology; D014806:Vitamin B 12 Deficiency / Q000150:complications / Q000378:metabolism / Q000503:physiopathology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016895:Culture Media, Serum-Free; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D006710:Homocysteine; D012436:S-Adenosylmethionine; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human