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

S-腺苷甲硫氨酸是一种营养：AD 中的遗传联系吗？

• 批准号: 7385896
• 负责人: THOMAS B. SHEA
• 金额: $ 16.04万
• 依托单位: UNIVERSITY OF MASSACHUSETTS LOWELL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7385896
• 关键词: Acetylcholine; Acetylcholinesterase Inhibitors; Address; Age; Age-Years; Aggressive behavior; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Antioxidants; Apolipoprotein E; Area; Behavioral; Biological Assay; Brain; Brain region; Cell Respiration; Choline; Clinical Research; Cognitive; Data; Development; Diet; Dietary Supplementation; Enzymes; Etiology; Event; Exhibits; Exploratory/Developmental Grant; Folate; Folic Acid Deficiency; Fostering; Genetic; Genetic Polymorphism; Genotype; Glutathione; Goals; Grant; Guidelines; Homocysteine; Homocystine; Human; Impaired cognition; Individual; Inflammation; Knockout Mice; Laboratories; Link; MTHFR gene; Mediating; Methionine; Methodology; Methylation; Methylenetetrahydrofolate reductase (NADPH); Modeling; Mus; Mutation; NIH Program Announcements; Natural regeneration; Nerve Degeneration; Neurons; Nutritional; Performance; Pharmaceutical Preparations; Preclinical Testing; Procedures; Protein Overexpression; Publications; Research Project Grants; Specific qualifier value; Subcategory; Supplementation; Techniques; Testing; Therapeutic; Transgenic Mice; abeta accumulation; alpha secretase; apolipoprotein E-3; apolipoprotein E-4; base; donepezil; drug discovery; familial Alzheimer disease; folic acid metabolism; gamma secretase; genetic risk factor; mouse model; neurofibrillary tangle formation; neuron loss; neuropathology; novel; novel strategies; nutrition; presenilin-1; prevent; research study; success; tau Proteins; transmethylation

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.

描述(由申请人提供)：阿尔茨海默病(AD)具有多因素的病因，包括营养和遗传风险因素。我们在小鼠身上的研究表明，主要的甲基供体S-腺苷蛋氨酸的缺乏会导致早老素1(PS1)的过度表达，从而增强伽玛分泌酶的活性，增加Abeta的水平。APOE-/-小鼠无论饮食如何都会降低SAM，叶酸缺乏会将SAM降低到临界水平，导致神经退化，这与PS-1诱导的家族性AD的加速发病一致，这些个体也携带ApoE4等位基因。我们还证明了SAM是谷胱甘肽介导的大脑氧化物种减少的重要辅助因素；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，我们证明了叶酸缺乏会由于SAM耗竭而减少大脑中的乙酰胆碱(ACH)，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可以恢复ACH水平(因为关键的甲基化事件阻止胆碱从大脑中运输出去)，防止认知衰退和减少攻击性。值得注意的是，在迷宫试验中补充SAM对表现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，而SAM可以补偿叶酸缺乏。 到目前为止，研究的重点是ApoE-/-小鼠作为衰老过程中氧化负担增加的模型。下一步至关重要的是研究SAM缺乏和饮食补充对AD小鼠模型(表达人ApoE4和E3和E2的小鼠；过度表达人APP的小鼠)和缺乏亚甲基四氢叶酸还原酶(亚甲基四氢叶酸还原酶在人类中存在多态，影响叶酸的使用并导致轻微的神经退化)的影响。这些小鼠将被剥夺叶酸？SAM，然后使用我们建立的程序检测认知表现、攻击性、ACH、PS-1表达、伽马分泌酶活性、Abeta和磷酸化tau。 我们建议的研究将进一步强调AD患者营养和遗传妥协之间的关键有害相互作用，并可能指向使用膳食SAM的治疗方法的发展。