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

点击翻译按钮获取中文摘要

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.