Dietary and genetic compromise in folate availability reduces acetylcholine, cognitive performance and increases aggression: Critical role of S-adenosyl methionine

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.

Plasma choline concentration varies with different dietary levels of vitamins B6, B12and folic acid in rats maintained on choline-adequate diets

“…Two different diets with varied vitamins B 6 , B 12 and folic acid contents were used: (1) B vitamin-poor; (2) B vitaminenriched. Diets were AIN-93M based (22) , isoenergetic and identical with respect to their protein, carbohydrate, fat, fibre, mineral and choline contents.…”

“…Diets were AIN-93M based (22) , isoenergetic and identical with respect to their protein, carbohydrate, fat, fibre, mineral and choline contents. The vitamin mix (AIN-93-VX) was prepared without vitamins B 6 , B 12 and folic acid and these vitamins were subsequently supplemented accordingly. Choline was added at AIN-93M levels, i.e.…”

“…Vitamins B 6 , B 12 and folate can support PEMT activity both by reducing homocysteine levels and by increasing methionine levels, resulting in an increased SAM:SAH ratio, and thus an increased methylation capacity. An alternative pathway for the regeneration of methionine from homocysteine in the liver is provided by the betaine-homocysteine methyltransferase pathway which involves the conversion of choline in the methyl donor betaine.…”

“…However, to date, research has concentrated on the effects of single B vitamins and on conditions of inadequate choline intake, but none of these reports has shown direct effects of B vitamins on plasma choline. The aim of the present experiment was to investigate the interdependence between dietary vitamins B 6 , B 12 and folate and plasma choline concentration in a dietary background of choline adequacy and mild B vitamin deficiency. The mild B vitamin deficiency was induced with a B vitamin-poor diet which was previously shown in our laboratory to induce a moderate increase in plasma homocysteine concentration (N. van Wijk and L. M. Broersen, unpublished results) and is thought to be relevant for conditions and/or diseases which are associated with mild B vitamin deficiencies and/or moderate increases in plasma homocysteine, such as ageing or Alzheimer's disease (AD) (20,21) .…”

“…The mild B vitamin deficiency was induced with a B vitamin-poor diet which was previously shown in our laboratory to induce a moderate increase in plasma homocysteine concentration (N. van Wijk and L. M. Broersen, unpublished results) and is thought to be relevant for conditions and/or diseases which are associated with mild B vitamin deficiencies and/or moderate increases in plasma homocysteine, such as ageing or Alzheimer's disease (AD) (20,21) . To this end, we measured plasma choline and homocysteine concentrations in rats that had consumed supplemental amounts of vitamins B 6 , B 12 and folic acid with recommended amounts of dietary choline after a mild B vitamin deficiency was induced.…”