First Posting: Folate and Glycolysis in Neuroprotection

I've been reading a lot about the effect that folic acid repletion has in augmenting the activities of glycolytic enzymes and decreasing the intracellular phosphoribosylpyrophosphate (PRPP) levels in some cell types. This is old research, and some of it is from the 1960s and 1970s. Some of it is more recent, but the research is relevant to an understanding of the mechanisms by which elevated blood levels of folic acid could protect against Alzheimer's disease and other dementias. There's a great deal of research on this, but here's a relevant article: http://www.ncbi.nlm.nih.gov/pubmed/10731508?dopt=Abstract

The effects of folic acid and methylcobalamin, which is the form of vitamin B12 that tends to not be problematic, on purine metabolism are puzzling, and I think the activation of glycolysis by folic acid may help explain some puzzling aspects of the research. What's interesting is that the activation of glycolysis, in response to increases in intracellular total folates, doesn't seem to occur under the conditions that one would expect to activate glycolysis. Drugs that lower the fasting blood sugar and are used to treat diabetes tend to increase the phosphorylation of AMP activated protein kinase (AMPK), either directly or as a secondary response to a decrease in ATP or increase in AMP (a decrease in the ATP/AMP ratio). Folic acid repletion tends to suppress a number of factors, including the inosine monophosphate (IMP) precursor AICAR, that would activate AMPK. There's other research showing that the folate-induced increase in glycolysis can occur without the kind of mitochondrial proliferation that one would expect to accompany AMPK activation, implying, albeit very indirectly, that folate repletion does not, in fact, produce AMPK activation.

I'll keep everyone posted on this *scintillating* topic. Suffice it to say that this could help explain the decreases in post-ischemic-stroke damage in animals given folate supplements. Folate "deficiency" was shown to more than double the volume of the infarct (damage) following an animal model of ischemic stroke (http://stroke.ahajournals.org/cgi/content/abstract/36/2/321), folate repletion tends to decrease intracellular AICAR levels, and AICAR has been shown to worsen post-stroke damage, in part, via AMPK activation (http://www.jbc.org/cgi/content/abstract/280/21/20493). The research on glycolysis, however, implies that the folate-mediated activation of glycolysis, even in the face of pre-stroke adequacy in the ATP/AMP levels, would occur independently, or somewhat independently, of a supposed folate-mediated decrease in AICAR. This activation of glycolysis in conjunction with adequate ATP is sort of generally associated with cellular growth and "trophic" effects. The activation of glycolysis could also help explain the inverse relationship between intracellular total folates and PRPP.