The S-adenosyl homocysteine hydrolase inhibitor 3-deaza-adenosine prevents oxidative damage and cognitive impairment following folate and vitamin E deprivation in a murine model of age-related, oxidative stress-induced neurodegeneration.

Deficiencies in folate promote neurodegeneration and potentiate the influence of other risk factors for neurodegeneration. This is accomplished at least in part by increasing levels of the neurotoxin homocysteine (HC). The S-adenosyl homocysteine (SAH) hydrolase inhibitor 3-deaza-adenosine (DZA) prevents HC accumulation following folate deprivation. We tested the ability of dietary supplementation with DZA to counteract the deleterious influence of folate deprivation. Folate deficiency has previously been shown to potentiate the impact of apolipoprotein E (ApoE); ApoE-/- mice deprived of folate demonstrated increased oxidative damage in brain tissue and impaired cognitive performance as compared to normal mice or to ApoE-/- mice receiving folate. Herein, we demonstrate that dietary supplementation with DZA prevented both the increase in oxidative damage and impaired cognition characteristic of ApoE-/- mice following folate deprivation. These findings suggest that manipulation of the methionine cycle by DZA can counteract folate deficiency. Because folate deprivation, increased HC, and apolipoprotein E deficiency are all risk factors for Alzheimer's disease, these findings also underscore that DZA might be useful in a therapeutic approach to delay neurodegeneration in Alzheimer's disease.

Folate deprivation induces neurodegeneration: roles of oxidative stress and increased homocysteine.

Clinical studies suggest a relationship between folate deficiency and neurological and disorders including Alzheimer's disease (AD). To investigate mechanisms underlying this association, we examined the consequences of folate deprivation on neuronal cultures. Culturing embryonic cortical neurons and differentiated SH-SY-5Y human neuroblastoma cells in folate-free medium induced neurodegenerative changes characteristic of those observed in AD, including increased cytosolic calcium, reactive oxygen species (ROS), phospho-tau and apoptosis. In accord with clinical studies, generation of the neurotoxic amino acid homocysteine (HC) was likely to contribute to these phenomena, since (1) a significant increase in HC was detected following folate deprivation, (2) addition of the inhibitor of HC formation, 3-deazaadenosine, both prevented HC formation and eliminated the increase in ROS that normally accompanied folate deprivation, (3) direct addition of HC in the presence of folate induced the neurotoxic effects that accompanied folate deprivation, and (4) an antagonist of NMDA channels that blocks HC-induced calcium influx also blocked calcium influx following folate deprivation. Folate deprivation decreased the reduced form of glutathione, indicating a depletion of oxidative buffering capacity. This line of reasoning was supported by an increase in glutathione and reduction in ROS following supplementation of folate-deprived cultures with the cell-permeant glutathione precursor, N-acetyl-L-cysteine, or vitamin E. Folate deprivation potentiated ROS and apoptosis induced by amyloid-beta, while folate supplementation at higher concentrations prevented generation of ROS by amyloid-beta, suggesting that folate levels modulate the extent of amyloid-beta neurotoxicity. These findings underscore the importance of folate metabolism in neuronal homeostasis and suggest that folate deficiency may augment AD neuropathology by increasing ROS and excitotoxicity via HC generation.