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 (9-12months 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 nicotinamine, 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.
