Here's a link to a piece on folic acid in relation to Alzheimer's. The article mentioning the possibility that physical exercise could produce higher serum folate levels sounds interesting, and it's a plausible and interesting way of explaining some of the variation in risk. I'll try to post the link to that article showing iron deficiency in animals lowered serum folate, and those types of things imply that the liver's ability, for example, to maintain the folate cycle (to export 5-methyltetrahydrofolate to the blood, essentially) by maintaining the cellular redox state may be impaired in a person who is sedentary and has poor insulin sensitivity, etc. The impact of iron would suggest that it's something to do with an improvement in mitochondrial functioning being a factor causing the folate cycle to be more normalized (in response to amelioration of Fe deficiency or exercise, given that both can improve the redox state). Iron deficiency has been shown to reduce mitochondrial complex I and complex IV activity in different tissues, etc. I'll look at the article they refer to. This blog piece has a quote from one of the researchers who was involved in that study:
http://www.tangledneuron.info/the_tangled_neuron/2007/07/folate-folic-ac.html
In a lot of the studies looking at serum folate in relation to disease risk factors, I think there's still a tendency to think of things in terms of deficiency vs. sufficiency of serum folate, etc. I know it's necessary to look at serum folate levels in large trials, but there can be depletion of cerebrospinal fluid MTHF and MTHF-responsive neurological symptoms in the presence of normal serum folate levels [as discussed in this article: (http://www.ncbi.nlm.nih.gov/pubmed/16365882)]. The disturbing thing about that article is that "cerebral folate deficiency" is not a single genetic disorder (though some cases apparently can be caused by mtDNA heteroplasmy) and can apparently be an "acquired" condition (and be due to autoantibodies to folate transporters, etc.). Before I read that article, I'd thought that it was a single genetic disorder or cluster of single-gene disorders that could produce a given phenotypic manifestation (low CSF MTHF and neurological abnormalities that are responsive to exogenous MTHF). This is something similar: (http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=3783183).
This article talks about the way an unknown percentage of serum folate, above 50 nM, is folic acid and not MTHF: (http://www3.interscience.wiley.com/journal/118671262/abstract). That article, in spite of some cautionary statements at the end of it, does provide support for the use of methylfolate. Apparently the mucosal epithelial cells in the intestinal tract can only reduce and methylate a few hundred micrograms of a given dose of folic acid (it requires either 2 or 4--I forget which--enzymatic cycles of dihydrofolate reductase to convert a single molecule of folic acid into tetrahydrofolate, for example--I think it's four). Those are big pieces of information. But a big thing in my mind is the extreme variability in serum folate responses, between studies, to different doses of folic acid. My old folic acid paper is not perfect, but I list some of the serum folate responses to given doses of folic acid. They're very inconsistent.
I doubt that the tissue folate levels are kept "constant" to any extent, as some articles suggest they are, in the face of variations in serum folate. This article (http://www.ncbi.nlm.nih.gov/pubmed/3461471) discusses, on the first page, the fact that the intracellular folate levels tend to be about 3 orders of magnitude (1,000) times the serum folate levels, and that's obviously true that cells concentrate and accumulate intracellular folates (THF, 5-MTHF, etc.) in the presence of a fixed, extracellular concentration of folic acid or MTHF or folinic acid. But then the authors make the statement that the intracellular concentration remains fixed in response to 20-40-fold increases in serum folate. This statement may have some degree of truth, if one uses the 10-20 nM starting point that the authors use (the "normal" serum folate levels). In that case, an increase from 20 to 400 or 800 nM serum folate may not increase the intracellular total folate concentration much in, say, astrocytes in the hippocampus. But does the absence of a major increase in the intracellular total folate concentration in an extrahepatic cell mean that the initial concentration (that failed to increase) was "normal" or "desirable" or was the 20 uM figure that is assumed to exist in every cell? It doesn't, but another issue is that 20 times 20 nM is still a fairly low serum folate level, at least from the standpoint of concentration-dependent effects of folate in cell culture studies. In this article (Karen Brown et al.), an extracellular folate level of 20 nM produces intracellular total folate levels that are much, much lower than those that occur in response to an extracellular folate level of 9.3 uM (when one does the calculation from ng/g protein or whatever, using the data, it works out to like 45 uM or something, I think, intracellularly, under the 9.3 uM condition and much less in the cells in the 20 nM cultures). And the cellular differentiation state and proliferation was shown to be much more robust at 9.3 uM extracellular folate than at 20 nM:
http://www.ncbi.nlm.nih.gov/pubmed/16469322
The authors also discuss the "large capacity" of the cells to accomodate extra folate coenzymes. One can say that the 9.3 uM concentration is very high and supraphysiological, but that's a separate issue. The point is that cells in the brain probably cannot regulate their intracellular folate levels in a "pristine" and rigid and predictable manner in response to changes in serum folate, and who's to say what the best intracellular total folate concentration is. A computational study showed that the folate cycle starts to fall apart at intracellular folate levels below 5 uM, but there are lots of issues to consider.
No comments:
Post a Comment