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

  • Renata H. Bahous
  • Marta Cosín-Tomás
  • Liyuan Deng
  • Daniel Leclerc
  • Olga Malysheva
  • Ming-Kai Ho
  • Mercè Pallàs
  • Perla Kaliman
  • Barry J. Bedell
  • Marie A. Caudill
  • Rima RozenEmail author


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.


Aging Brain Choline Epigenetics Folate MTHFR 



We thank Dr. Nancy Lévesque for her help in conducting the experiments. We also thank Marie-Julie Allard and Mathilde Chevin (McGill University) for assistance with methodologies.

Funding Information

This work was supported by the Canadian Institutes of Health Research (MOP-43232 to RR). RHB is the recipient of a Doctoral Award from the Fonds de Recherche du Québec-Santé. MCT is the recipient of a Predoctoral Fellowship from MINECO (FPU 2013) and Post-Doctoral Award from the Fonds de Recherche du Québec-Santé. The Research Institute is supported by a Center’s grant from the Fonds de Recherche du Québec-Santé.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2018_1375_MOESM1_ESM.docx (150 kb)
ESM 1 (DOCX 150 kb)


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Authors and Affiliations

  • Renata H. Bahous
    • 1
  • Marta Cosín-Tomás
    • 1
  • Liyuan Deng
    • 1
  • Daniel Leclerc
    • 1
  • Olga Malysheva
    • 2
  • Ming-Kai Ho
    • 3
  • Mercè Pallàs
    • 4
  • Perla Kaliman
    • 5
  • Barry J. Bedell
    • 3
  • Marie A. Caudill
    • 2
  • Rima Rozen
    • 1
    Email author
  1. 1.Departments of Human Genetics and PediatricsResearch Institute of the McGill University Health CentreMontrealCanada
  2. 2.Division of Nutritional Sciences and GenomicsCornell UniversityIthacaUSA
  3. 3.Department of Neurology and NeurosurgeryMcGill UniversityMontrealCanada
  4. 4.Pharmacology Unit, Faculty of Pharmacy, Institut de Neurociència Universitat de Barcelona (IBUB)Nucli Universitari de PedralbesBarcelonaSpain
  5. 5.Institute of Biomedical Investigation of BarcelonaSpanish National Research CouncilBarcelonaSpain

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