Early Manifestations of Brain Aging in Mice Due to Low Dietary Folate and Mild MTHFR Deficiency

Mol Neurobiol. 2019 Jun;56(6):4175-4191. doi: 10.1007/s12035-018-1375-3. Epub 2018 Oct 4.


Folate is an important B vitamin required for methylation reactions, nucleotide and neurotransmitter synthesis, and maintenance of homocysteine at nontoxic levels. Its metabolism is tightly linked to that of choline, a precursor to acetylcholine and membrane phospholipids. Low folate intake and genetic variants in folate metabolism, such as the methylenetetrahydrofolate reductase (MTHFR) 677 C>T polymorphism, have been suggested to impact brain function and increase the risk for cognitive decline and late-onset Alzheimer's disease. Our study aimed to assess the impact of genetic and nutritional disturbances in folate metabolism, and their potential interaction, on features of cognitive decline and brain biochemistry in a mouse model. Wild-type and Mthfr+/- mice, a model for the MTHFR 677 C>T polymorphism, were fed control or folate-deficient diets from weaning until 8 and 10 months of age. We observed short-term memory impairment measured by the novel object paradigm, altered transcriptional levels of synaptic markers and epigenetic enzymes, as well as impaired choline metabolism due to the Mthfr+/- genotype in cortex or hippocampus. We also detected changes in mRNA levels of Presenillin-1, neurotrophic factors, one-carbon metabolic and epigenetic enzymes, as well as reduced levels of S-adenosylmethionine and acetylcholine, due to the folate-deficient diet. These findings shed further insights into the mechanisms by which genetic and dietary folate metabolic disturbances increase the risk for cognitive decline and suggest that these mechanisms are distinct.

Keywords: Aging; Brain; Choline; Epigenetics; Folate; MTHFR.

MeSH terms

  • Aging / pathology*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Anxiety / complications
  • Anxiety / physiopathology
  • Brain / pathology*
  • Brain / physiopathology
  • Cell Survival
  • Cerebral Cortex / pathology
  • Cerebral Cortex / physiopathology
  • Choline / metabolism
  • CpG Islands / genetics
  • DNA Methylation / genetics
  • Diet*
  • Epigenesis, Genetic
  • Folic Acid / metabolism*
  • Glutamic Acid / metabolism
  • Homocystinuria / complications*
  • Homocystinuria / physiopathology
  • Liver / metabolism
  • Male
  • Memory Disorders / complications
  • Memory Disorders / physiopathology
  • Memory, Short-Term
  • Methylation
  • Methylenetetrahydrofolate Reductase (NADPH2) / deficiency*
  • Mice, Inbred BALB C
  • Muscle Spasticity / complications*
  • Muscle Spasticity / physiopathology
  • Nerve Growth Factors / metabolism
  • Neurons / pathology
  • Phospholipids / metabolism
  • Psychotic Disorders / complications
  • Psychotic Disorders / physiopathology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • S-Adenosylmethionine / metabolism
  • Synaptic Transmission


  • Amyloid beta-Peptides
  • Nerve Growth Factors
  • Phospholipids
  • RNA, Messenger
  • Glutamic Acid
  • S-Adenosylmethionine
  • Folic Acid
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Choline

Supplementary concepts

  • Methylenetetrahydrofolate reductase deficiency