B-vitamin deprivation induces hyperhomocysteinemia and brain S-adenosylhomocysteine, depletes brain S-adenosylmethionine, and enhances PS1 and BACE expression and amyloid-beta deposition in mice.
Etiological and molecular studies on the sporadic form of Alzheimer's disease have yet to determine the underlying mechanisms of neurodegeneration. Hyperhomocysteinemia is associated with Alzheimer's disease, and has been hypothesized to promote neurodegeneration, by inhibiting brain methylation activity. The aim of this work was to determine whether a combined folate, B12 and B6 dietary deficiency, would induce amyloid-beta overproduction, and to study the mechanisms linking vitamin deficiency, hyperhomocysteinemia and amyloidogenesis in TgCRND8 and 129Sv mice. We confirmed that B-vitamin deprivation induces hyperhomocysteinemia and imbalance of S-adenosylmethionine and S-adenosylhomocysteine. This effect was associated with PS1 and BACE up-regulation and amyloid-beta deposition. Finally, we detected intraneuronal amyloid-beta and a slight cognitive impairment in a water maze task at a pre-plaque age, supporting the hypothesis of early pathological function of intracellular amyloid. Collectively, these findings are consistent with the hypothesis that abnormal methylation in association with hyperhomocysteinemia may contribute to Alzheimer's disease.
Fuso
Andrea
A
Department of Surgery P. Valdoni, Sapienza University of Rome, Italy.
Nicolia
Vincenzina
V
Cavallaro
Rosaria A
RA
Ricceri
Laura
L
D'Anselmi
Fabrizio
F
Coluccia
Pierpaolo
P
Calamandrei
Gemma
G
Scarpa
Sigfrido
S
D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis* / Q000235:genetics; D001921:Brain / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000502:physiology; D020138:Hyperhomocysteinemia / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D053764:Presenilin-1 / Q000096:biosynthesis* / Q000235:genetics; D012435:S-Adenosylhomocysteine / Q000378:metabolism*; D012436:S-Adenosylmethionine / Q000172:deficiency* / Q000235:genetics; D014804:Vitamin B Deficiency / Q000150:complications / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D053764:Presenilin-1; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human