S-adenosylmethionine/homocysteine cycle alterations modify DNA methylation status with consequent deregulation of PS1 and BACE and beta-amyloid production
S-adenosylmethionine/homocysteine cycle alterations modify DNA methylation status with consequent deregulation of PS1 and BACE and beta-amyloid production
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DOI：
10.1016/j.mcn.2004.09.007
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发表时间：
2005-01-01
影响因子：
3.5
通讯作者：
Scarpa, S
中科院分区：
文献类型：
--
作者：
Fuso, A;Seminara, L;Scarpa, S
少数疾病的特点是高同型半胱氨酸（HCY）和低叶酸和维生素B12的血液水平。阿尔茨海默病（AD）就是其中之一。已经表明DNA甲基化通过调节早老素1（Presenilin 1，PS1）的表达参与淀粉样前体蛋白（amyloid precursor protein，APP）的加工和β-淀粉样蛋白（beta-amyloid，Abeta）的产生，并且外源性S-腺苷甲硫氨酸（S-adenosylmethionine，SAM）可以沉默该基因，从而减少A的产生。在这里，我们证明，BACE（β-分泌酶），以及PSI，是由甲基化和叶酸和维生素B12在培养基中的减少，可以导致SAM水平的降低，从而增加早老素1和BACE水平，并增加Abeta生产。将SAM同时施用到缺陷培养基中可以恢复正常的基因表达，从而降低Abeta水平。使用剥夺培养基旨在模拟AD发作中涉及的轻度营养缺乏。(C)2004年爱思唯尔公司All rights reserved.
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 (Abeta) production through the regulation of Presenilin1 (PS1) expression and that exogenous S-adenosylmethionine (SAM) can silence the gene reducing A production. Here we demonstrate that BACE (beta-secretase), as well as PSI, 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 Abeta production. The simultaneous administration of SAM to the deficient medium can restore the normal gene expression, thus reducing the Abeta levels. The use of deprived medium was intended to mimic a mild nutritional deficit involved in the onset of AD. (C) 2004 Elsevier Inc. All rights reserved.