B-vitamin deprivation induces hyperhomocysteinemia and brain S-adenosylhomocysteine, depletes brain S-adenosylmethionine, and enhances PS1 and BACE expression and amyloid-β deposition in mice
B-vitamin deprivation induces hyperhomocysteinemia and brain S-adenosylhomocysteine, depletes brain S-adenosylmethionine, and enhances PS1 and BACE expression and amyloid-β deposition in mice
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DOI：
10.1016/j.mcn.2007.12.018
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发表时间：
2008-04-01
影响因子：
3.5
通讯作者：
Scarpa, Sigfrido
中科院分区：
文献类型：
--
作者：
Fuso, Andrea;Nicolia, Vincenzina;Scarpa, Sigfrido
对散发性阿尔茨海默病的病因学和分子学研究尚未确定神经变性的潜在机制。高同型半胱氨酸血症与阿尔茨海默氏病有关，并被假设通过抑制脑甲基化活性促进神经退行性变。这项工作的目的是确定联合叶酸，B12和B6饮食缺乏是否会诱导淀粉样蛋白-β过度产生，并研究TgCRND 8和129Sv小鼠中维生素缺乏，高同型半胱氨酸血症和淀粉样蛋白生成的机制。我们证实，B族维生素剥夺诱导高同型半胱氨酸血症和S-腺苷甲硫氨酸和S-腺苷同型半胱氨酸的失衡。这种作用与PS1和BACE上调和淀粉样β蛋白沉积有关。最后，我们检测到神经元内淀粉样蛋白-P和轻微的认知障碍，在水迷宫任务在斑块前的年龄，支持细胞内淀粉样蛋白的早期病理功能的假设。总的来说，这些发现与高同型半胱氨酸血症相关的异常甲基化可能导致阿尔茨海默病的假设一致。(c)2007年爱思唯尔公司All rights reserved.
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-P 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. (c) 2007 Elsevier Inc. All rights reserved.