Is S-adenosyl Methionine a Nutrition: Genetic Link in AD?

描述（由申请人提供）：阿尔茨海默病（AD）具有多因素病因，包括营养和遗传风险因素。我们对小鼠的研究表明，s -腺苷蛋氨酸（SAM，主要的甲基供体）缺乏会促进早老素1 （PS1）的过度表达，从而增强γ -分泌酶活性并增加β水平。无论饮食如何，ApoE-/-小鼠的SAM都减少了，叶酸缺乏将SAM降低到临界水平，导致神经变性，这与ps -1诱导的家族性AD在那些携带ApoE4等位基因的个体中加速发病一致。我们还证明，SAM是谷胱甘肽介导的脑内氧化物质减少的重要辅助因子；ApoE-/-小鼠缺乏SAM可阻止谷胱甘肽的使用，而膳食补充SAM可恢复谷胱甘肽的使用并防止氧化损伤。最后，也是最重要的是，我们证明叶酸缺乏会减少大脑中乙酰胆碱（ACH），这是由于SAM的消耗，这伴随着迷宫试验中认知表现的下降和攻击性的增加。膳食中补充SAM可恢复乙酰胆碱水平（因为关键的甲基化事件阻止胆碱从大脑中转运出去），防止认知能力下降并减少攻击性。值得注意的是，在迷宫试验中，补充SAM对性能的影响与乙酰胆碱酯酶抑制剂多奈哌齐相当。这些数据表明叶酸缺乏增强了AD的多种遗传危险因素，SAM可以弥补叶酸缺乏。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) has a multifactoral etiology encompassing nutritional and genetic risk factors. Our studies in mice show that deficiency in S-adenosyl methionine (SAM, the major methyl donor) fosters presenilin 1 (PS1) overexpression, which enhances gamma-secretase activity and increases Abeta levels. ApoE-/- mice have reduced SAM regardless of diet, and folate-deficiency reduces SAM to critical levels, leading to neurodegeneration, consistent with the hastened onset of PS-1-induced familial AD in those individuals also harboring the ApoE4 allele. We have also demonstrated that SAM is an essential co-factor for glutathione-mediated reduction of oxidative species in brain; SAM deficiency in ApoE-/- mice prevented glutathione usage, while dietary supplementation with SAM restored glutathione usage and prevented oxidative damage. Finally, and most importantly, we demonstrate that folate deficiency reduces acetylcholine (ACH) in brain due to SAM depletion, which is accompanied by a decline in cognitive performance in maze trials and increased aggression. Dietary SAM supplementation restores ACH levels (since key methylation events prevent choline transport out of brain), prevents cognitive decline and reduces aggression. Notably, SAM supplementation on performance in maze trials equals that of the acetylcholinesterase inhibitor donepezil. These data indicate that folate deficiency potentiates multiple genetic risk factors for AD and that SAM can compensate for folate deficiency. Studies until now have focused on ApoE-/- mice as a model for increased oxidative burden in aging. An essential next step is to examine the impact of SAM deficiency and dietary supplementation in mouse models of AD, (mice expressing human ApoE4 vs. E3 and E2; mice overexpressing human APP) and in mice lacking methylene tetrahydrofolate reductase (polymorphisms of which exist in humans, compromise folate usage and induce mild neurodegeneration). These mice will be deprived of folate ¿ SAM, then assayed for cognitive performance, aggression, ACH, PS-1 expression, gamma-secretase activity, Abeta and phospho-tau using our established procedures. Our proposed studies will further underscore crucial deleterious interplay between nutritional and genetic compromise in AD and may point towards the development of therapeutic approaches using dietary SAM.