ABSTRACT
Folate deficiency has been associated with age-related neurodegeneration. One direct consequence of folate deficiency is a decline in the major methyl donor, S-adenosyl methionine (SAM). We demonstrate herein that pro-oxidant stress and dietary folate deficiency decreased levels of acetylcholine and impaired cognitive performance to various degrees in normal adult mice (9-12 months of age, adult mice heterozygously lacking 5',10'-methylene tetrahydrofolate reductase, homozygously lacking apolipoprotein E, or expressing human ApoE2, E3 or E4, and aged (2-2.5 year old) normal mice. Dietary supplementation with SAM in the absence of folate restored acetylcholine levels and cognitive performance to respective levels observed in the presence of folate. Increased aggressive behavior was observed among some but not all genotypes when maintained on the deficient diet, and was eliminated in all cases supplementation with SAM. Folate deficiency decreased levels of choline and N-methyl nicotinamide, while dietary supplementation with SAM increased methylation of nicotinamide to generate N-methyl nicotinamide and restored choline levels within brain tissue. Since N-methyl nicotinamide inhibits choline transport out of the central nervous system, and choline is utilized as an alternative methyl donor, these latter findings suggest that SAM may maintain acetylcholine levels in part by maintaining availability of choline. These findings suggest that dietary supplementation with SAM represents a useful therapeutic approach for age-related neurodegeneration which may augment pharmacological approaches to maintain acetylcholine levels, in particular during dietary or genetic compromise in folate usage.
Subject(s)
Acetylcholine/metabolism , Aggression/drug effects , Cognition/drug effects , Folic Acid Deficiency/physiopathology , Folic Acid/metabolism , S-Adenosylmethionine/pharmacology , 5,10-Methylenetetrahydrofolate Reductase (FADH2)/deficiency , Aging , Animals , Apolipoproteins E/deficiency , Cognition/physiology , Folic Acid/administration & dosage , Folic Acid/pharmacokinetics , Folic Acid Deficiency/metabolism , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Oxidation-Reduction , Oxidative Stress/drug effects , Oxidative Stress/physiology , Random Allocation , S-Adenosylmethionine/metabolismABSTRACT
Clinical manifestation of Alzheimer's disease may depend upon interaction among its risk factors. Apolipoprotein E-deficient mice undergo oxidative damage and cognitive impairment when deprived of folate. We demonstrate herein that these mice were depleted in the methyl donor S-adenosyl methionine (SAM), which inhibited glutathione S-transferase, since this enzyme requires methylation of oxidative species prior to glutathione-dependent reduction. Dietary supplementation with SAM alleviated neuropathology. Since SAM deficiency promotes presenilin-1 overexpression, which increases gamma-secretase expression and Abeta generation, these findings directly link nutritional deficiency and genetic risk factors, and support supplementation with SAM for Alzheimer's therapy.
Subject(s)
Adenosine/analogs & derivatives , Alzheimer Disease/prevention & control , Ethionine/analogs & derivatives , Gene Expression Regulation, Enzymologic , Glutathione Transferase/antagonists & inhibitors , Oxidative Stress , Adenosine/deficiency , Adenosine/therapeutic use , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Animals , Apolipoproteins E/deficiency , Apolipoproteins E/genetics , Disease Models, Animal , Enzyme Inhibitors , Ethionine/deficiency , Ethionine/therapeutic use , Glutathione Transferase/genetics , Mice , Mice, Knockout , Risk Factors , Vitamin E DeficiencyABSTRACT
Increased oxidative stress, which can arise from dietary, environmental and/or genetic sources, contributes to the decline in cognitive performance during normal aging and in neurodegenerative conditions such as Alzheimer's disease. Supplementation with fruits and vegetables that are high in antioxidant potential can compensate for dietary and/or genetic deficiencies that promote increased oxidative stress. We have recently demonstrated that apple juice concentrate (AJC) prevents the increase in oxidative damage to brain tissue and decline in cognitive performance observed when transgenic mice lacking apolipoprotein E (ApoE-/-) are maintained on a vitamin-deficient diet and challenged with excess iron (included in the diet as a pro-oxidant). However, the mechanism by which AJC provided neuroprotection was not conclusively determined. Herein, we demonstrate that supplementation with AJC also prevents the compensatory increases in glutathione synthase transcription and activity that otherwise accompany maintenance of ApoE-/- mice on this vitamin-free diet in the presence of iron. Inclusion of the equivalent composition and concentration of sugars of AJC did not prevent these increases. These findings provide further evidence that the antioxidant potential of AJC can compensate for dietary and genetic deficiencies that otherwise promote neurodegeneration.