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Folate, mitochondria, ROS, and the aging brain

      To the Editor:
      I read with interest the article by Kado et al.
      • Kado D.M.
      • Karlamangla A.S.
      • Huang M.H.
      • et al.
      Homocysteine versus the vitamins folate, B6, and B12 as predictors of cognitive function and decline in older high-functioning adults MacArthur Studies of Successful Aging.
      They found that low folate levels are associated with cognitive decline in older adults. While reading the research literature on folate, I noticed another recently published article
      • Crott J.W.
      • Choi S.W.
      • Branda R.F.
      • Mason J.B.
      Accumulation of mitochondrial DNA deletions is age, tissue and folate-dependent in rats.
      that might have a bearing on the work of Kado et al. One may infer from it an additional mechanism by which low folate levels could cause cognitive decline.
      Crott et al
      • Crott J.W.
      • Choi S.W.
      • Branda R.F.
      • Mason J.B.
      Accumulation of mitochondrial DNA deletions is age, tissue and folate-dependent in rats.
      found that folate reduced the level of 4.8 kb deletions in mitochondrial (Mt) DNA in older rats. They attributed this to folate attenuating the misincorporation of uracil into DNA, thus preventing double-strand breaks from the uracil excision process.
      The 4.8 kb deletion in rats is homologous to the common 4977 bp deletion in humans.
      • Crott J.W.
      • Choi S.W.
      • Branda R.F.
      • Mason J.B.
      Accumulation of mitochondrial DNA deletions is age, tissue and folate-dependent in rats.
      There is an accumulation of the common 4977 bp deletion in the aging human brain.
      • Blanchard B.J.
      • Park T.
      • Fripp W.J.
      • et al.
      A mitochondrial DNA deletion in normally aging and in Alzheimer brain tissue.
      This deletion removes 30% of the MtDNA molecule, comprising the mitochondria’s respiratory capacity.
      • Storm T.
      • Rath S.
      • Mohamed S.A.
      • et al.
      Mitotic brain cells are just as prone to mitochondrial deletions as neurons a large-scale single-cell PCR study of the human caudate nucleus.
      It also results in oxidative stress
      • Wei Y.H.
      • Lee C.F.
      • Lee H.C.
      • et al.
      Increases of mitochondrial mass and mitochondrial genome in association with enhanced oxidative stress in human cells harboring 4,977 BP-deleted mitochondrial DNA.
      from reactive oxygen species (ROS).
      • Lu C.Y.
      • Lee H.C.
      • Fahn H.J.
      • Wei Y.H.
      Oxidative damage elicited by imbalance of free radical scavenging enzymes is associated with large-scale mtDNA deletions in aging human skin.
      The excess generation of ROS in the hippocampal neurons of older adults has been implicated in interfering with memory formation.
      • Knapp L.T.
      • Klann E.
      Role of reactive oxygen species in hippocampal long-term potentiation contributory or inhibitory?.
      • Serrano F.
      • Klann E.
      Reactive oxygen species and synaptic plasticity in the aging hippocampus.
      Long-term potentiation (LTP) is a form of synaptic plasticity involved in learning and memory. Excessive amounts of ROS block LTP by activating the stress-activated protein kinases JNK and p38 MAPK.
      In addition, ROS have been implicated in Alzheimer’s disease because they have a pro-aggregating effect on beta/A4 protein and the C-terminal fragment of amyloid precursor.
      • Benzi G.
      • Moretti A.
      Are reactive oxygen species involved in Alzheimer’s disease?.
      This may be an additional mechanism by which low folate levels contribute to cognitive decline in older adults.

      References

        • Kado D.M.
        • Karlamangla A.S.
        • Huang M.H.
        • et al.
        Homocysteine versus the vitamins folate, B6, and B12 as predictors of cognitive function and decline in older high-functioning adults.
        Am J Med. 2005; 118: 161-167
        • Crott J.W.
        • Choi S.W.
        • Branda R.F.
        • Mason J.B.
        Accumulation of mitochondrial DNA deletions is age, tissue and folate-dependent in rats.
        Mutat Res. 2005; 570: 63-70
        • Blanchard B.J.
        • Park T.
        • Fripp W.J.
        • et al.
        A mitochondrial DNA deletion in normally aging and in Alzheimer brain tissue.
        Neuroreport. 1993; 4: 799-802
        • Storm T.
        • Rath S.
        • Mohamed S.A.
        • et al.
        Mitotic brain cells are just as prone to mitochondrial deletions as neurons.
        Exp Gerontol. 2002; 37: 1389-1400
        • Wei Y.H.
        • Lee C.F.
        • Lee H.C.
        • et al.
        Increases of mitochondrial mass and mitochondrial genome in association with enhanced oxidative stress in human cells harboring 4,977 BP-deleted mitochondrial DNA.
        Ann N Y Acad Sci. 2001; 928: 97-112
        • Lu C.Y.
        • Lee H.C.
        • Fahn H.J.
        • Wei Y.H.
        Oxidative damage elicited by imbalance of free radical scavenging enzymes is associated with large-scale mtDNA deletions in aging human skin.
        Mutat Res. 1999; 423: 11-21
        • Knapp L.T.
        • Klann E.
        Role of reactive oxygen species in hippocampal long-term potentiation.
        J Neurosci Res. 2002; 70: 1-7
        • Serrano F.
        • Klann E.
        Reactive oxygen species and synaptic plasticity in the aging hippocampus.
        Ageing Res Rev. 2004; 3: 431-443
        • Benzi G.
        • Moretti A.
        Are reactive oxygen species involved in Alzheimer’s disease?.
        Neurobiol Aging. 1995; 16: 661-674

      Linked Article

      • The Reply
        The American Journal of MedicineVol. 118Issue 10
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          Ms. Ross suggests an intriguing hypothesis of how low folate might contribute to cognitive decline in older persons. She speculates that low folate might lead specifically to mitochondrial DNA deletions and therefore potentiate the generation of reactive oxygen species that could ultimately result in worse cognitive function. We appreciate the interest Ms. Ross has taken in our study by suggesting this pathway. However, there is little evidence to support these speculations relative to other more plausible mechanisms such as impaired DNA methylation in the brain or cerebrovascular damage.
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