Skip to main content

Advertisement

SpringerLink
Log in

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

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Moore K, Hughes CF, Ward M, Hoey L, McNulty H (2018) Diet, nutrition and the ageing brain: current evidence and new directions. Proc Nutr Soc 77:1–12. https://doi.org/10.1017/S0029665117004177

    Article  Google Scholar 

  2. Bishop NA, Lu T, Yankner BA (2010) Neural mechanisms of ageing and cognitive decline. Nature 464(7288):529–535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153(6):1194–1217

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Jagust W (2013) Vulnerable neural systems and the borderland of brain aging and neurodegeneration. Neuron 77(2):219–234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Krstic D, Knuesel I (2013) Deciphering the mechanism underlying late-onset Alzheimer disease. Nat Rev Neurol 9(1):25–34

    Article  CAS  PubMed  Google Scholar 

  6. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR et al (2011) Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7(3):280–292

    Article  PubMed  PubMed Central  Google Scholar 

  7. Imtiaz B, Tolppanen A-M, Kivipelto M, Soininen H (2014) Future directions in Alzheimer’s disease from risk factors to prevention. Biochem Pharmacol 88(4):661–670

    Article  CAS  PubMed  Google Scholar 

  8. Deckers K, Boxtel MP, Schiepers OJ, Vugt M, Muñoz Sánchez JL, Anstey KJ, Brayne C, Dartigues JF et al (2015) Target risk factors for dementia prevention: a systematic review and Delphi consensus study on the evidence from observational studies. Int J Geriatr Psychiatry 30(3):234–246

    Article  PubMed  Google Scholar 

  9. Lopes da Silva S, Vellas B, Elemans S, Luchsinger J, Kamphuis P, Yaffe K, Sijben J, Groenendijk M et al (2013) Plasma nutrient status of patients with Alzheimer’s disease: systematic review and meta-analysis. Alzheimers Dement

  10. Setién-Suero E, Suárez-Pinilla M, Suarez-Pinilla P, Crespo-Facorro B, Ayesa-Arriola R (2016) Homocysteine and cognition: a systematic review of 111 studies. Neurosci Biobehav Rev 69:280–298

    Article  PubMed  CAS  Google Scholar 

  11. Laumet G, Chouraki V, Grenier-Boley B, Legry V, Heath S, Zelenika D, Fievet N, Hannequin D et al (2010) Systematic analysis of candidate genes for Alzheimer’s disease in a French, genome-wide association study. J Alzheimers Dis 20(4):1181–1188

    Article  CAS  PubMed  Google Scholar 

  12. Rajagopalan P, Jahanshad N, Stein JL, Hua X, Madsen SK, Kohannim O, Hibar DP, Toga AW et al (2012) Common folate gene variant, MTHFR C677T, is associated with brain structure in two independent cohorts of people with mild cognitive impairment. Neuroimage Clin 1(1):179–187

    Article  PubMed  PubMed Central  Google Scholar 

  13. Georgieff MK (2007) Nutrition and the developing brain: nutrient priorities and measurement. Am J Clin Nutr 85(2):614S–620S

    CAS  PubMed  Google Scholar 

  14. Reynolds E (2006) Vitamin B12, folic acid, and the nervous system. Lancet Neurol 5(11):949–960

    Article  CAS  PubMed  Google Scholar 

  15. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M et al (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10(1):111–113

    Article  CAS  PubMed  Google Scholar 

  16. Meadows DN, Pyzik M, Wu Q, Torre S, Gros P, Vidal SM, Rozen R (2014) Increased resistance to malaria in mice with methylenetetrahydrofolate reductase (Mthfr) deficiency suggests a mechanism for selection of the MTHFR 677C> T (c. 665C> T) variant. Hum Mutat 35(5):594–600

    Article  CAS  PubMed  Google Scholar 

  17. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D’Agostino RB, Wilson PW, Wolf PA (2002) Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med 346(7):476–483

    Article  CAS  PubMed  Google Scholar 

  18. Wald DS, Kasturiratne A, Simmonds M (2010) Effect of folic acid, with or without other B vitamins, on cognitive decline: meta-analysis of randomized trials. Am J Med 123(6):522–527.e522

    Article  CAS  PubMed  Google Scholar 

  19. Devlin AM, Arning E, Bottiglieri T, Faraci FM, Rozen R, Lentz SR (2004) Effect of Mthfr genotype on diet-induced hyperhomocysteinemia and vascular function in mice. Blood 103(7):2624–2629

    Article  CAS  PubMed  Google Scholar 

  20. Chen Z, Karaplis AC, Ackerman SL, Pogribny IP, Melnyk S, Lussier-Cacan S, Chen MF, Pai A et al (2001) Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. Hum Mol Genet 10(5):433–443

    Article  CAS  PubMed  Google Scholar 

  21. Fuso A, Nicolia V, Pasqualato A, Fiorenza MT, Cavallaro RA, Scarpa S (2011) Changes in Presenilin 1 gene methylation pattern in diet-induced B vitamin deficiency. Neurobiol Aging 32(2):187–199

    Article  CAS  PubMed  Google Scholar 

  22. Chan A, Tchantchou F, Rogers EJ, Shea TB (2009) Dietary deficiency increases presenilin expression, gamma-secretase activity, and Abeta levels: potentiation by ApoE genotype and alleviation by S-adenosyl methionine. J Neurochem 110(3):831–836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Caudill MA (2009) Folate and choline interrelationships: metabolic and potential health implications. In: Bailey LB (ed) Folate in health and disease, vol 1, 2nd edn. CRC Press, USA, pp. 449–465

    Google Scholar 

  24. Yan J, Wang W, Gregory JF 3rd, Malysheva O, Brenna JT, Stabler SP, Allen RH, Caudill MA (2011) MTHFR C677T genotype influences the isotopic enrichment of one-carbon metabolites in folate-compromised men consuming d9-choline. Am J Clin Nutr 93(2):348–355

    Article  CAS  PubMed  Google Scholar 

  25. Ganz AB, Shields K, Fomin VG, Lopez YS, Mohan S, Lovesky J, Chuang JC, Ganti A et al (2016) Genetic impairments in folate enzymes increase dependence on dietary choline for phosphatidylcholine production at the expense of betaine synthesis. FASEB J 30(10):3321–3333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Jadavji NM, Deng L, Leclerc D, Malysheva O, Bedell BJ, Caudill MA, Rozen R (2012) Severe methylenetetrahydrofolate reductase deficiency in mice results in behavioral anomalies with morphological and biochemical changes in hippocampus. Mol Genet Metab 106(2):149–159

    Article  CAS  PubMed  Google Scholar 

  27. Troen AM, Chao WH, Crivello NA, D’Anci KE, Shukitt-Hale B, Smith DE, Selhub J, Rosenberg IH (2008) Cognitive impairment in folate-deficient rats corresponds to depleted brain phosphatidylcholine and is prevented by dietary methionine without lowering plasma homocysteine. J Nutr 138(12):2502–2509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Selley ML (2007) A metabolic link between S-adenosylhomocysteine and polyunsaturated fatty acid metabolism in Alzheimer’s disease. Neurobiol Aging 28(12):1834–1839

    Article  CAS  PubMed  Google Scholar 

  29. Zhuo J-M, Praticò D (2010) Acceleration of brain amyloidosis in an Alzheimer’s disease mouse model by a folate, vitamin B6 and B12-deficient diet. Exp Gerontol 45(3):195–201

    Article  CAS  PubMed  Google Scholar 

  30. Chan A, Tchantchou F, Graves V, Rozen R, Shea T (2008) Dietary and genetic compromise in folate availability reduces acetylcholine, cognitive performance and increases aggression: critical role of S-adenosyl methionine. J Nutr Health Aging 12(4):252–261

    Article  CAS  PubMed  Google Scholar 

  31. Knock E, Deng L, Wu Q, Lawrance AK, Wang XL, Rozen R (2008) Strain differences in mice highlight the role of DNA damage in neoplasia induced by low dietary folate. J Nutr 138(4):653–658

    Article  CAS  PubMed  Google Scholar 

  32. McQuown SC, Barrett RM, Matheos DP, Post RJ, Rogge GA, Alenghat T, Mullican SE, Jones S et al (2011) HDAC3 is a critical negative regulator of long-term memory formation. J Neurosci 31(2):764–774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. De Jager PL, Srivastava G, Lunnon K, Burgess J, Schalkwyk LC, Yu L, Eaton ML, Keenan BT et al (2014) Alzheimer’s disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nat Neurosci 17(9):1156–1163

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Lipton SA, Kim W-K, Choi Y-B, Kumar S, D’Emilia DM, Rayudu PV, Arnelle DR, Stamler JS (1997) Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proc Natl Acad Sci 94(11):5923–5928

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhang Y, Li P, Feng J, Wu M (2016) Dysfunction of NMDA receptors in Alzheimer’s disease. Neurol Sci 37(7):1039–1047

    Article  PubMed  PubMed Central  Google Scholar 

  36. Chow VW, Mattson MP, Wong PC, Gleichmann M (2010) An overview of APP processing enzymes and products. NeuroMolecular Med 12(1):1–12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Podcasy JL, Epperson CN (2016) Considering sex and gender in Alzheimer disease and other dementias. Dialogues Clin Neurosci 18(4):437

    PubMed  PubMed Central  Google Scholar 

  38. Gilbody S, Lewis S, Lightfoot T (2007) Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review. Am J Epidemiol 165(1):1–13

    Article  PubMed  Google Scholar 

  39. Wang Y, Xu S, Cao Y, Xie Z, Lai C, Ji X, Bi J (2014) Folate deficiency exacerbates apoptosis by inducing hypomethylation and resultant overexpression of DR4 together with altering DNMTs in Alzheimer’s disease. Int J Clin Exp Med 7(8):1945–1957

    PubMed  PubMed Central  Google Scholar 

  40. Ghoshal K, Li X, Datta J, Bai S, Pogribny I, Pogribny M, Huang Y, Young D et al (2006) A folate- and methyl-deficient diet alters the expression of DNA methyltransferases and methyl CpG binding proteins involved in epigenetic gene silencing in livers of F344 rats. J Nutr 136(6):1522–1527

    Article  CAS  PubMed  Google Scholar 

  41. Ding Y, He J, Liu X, Chen X, Long C, Wang Y (2012) Expression of DNA methyltransferases in the mouse uterus during early pregnancy and susceptibility to dietary folate deficiency. Reproduction:REP-12-0006

  42. Bottiglieri T, Godfrey P, Flynn T, Carney M, Toone B, Reynolds E (1990) Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine. J Neurol Neurosurg Psychiatry 53(12):1096–1098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Dayon L, Guiraud SP, Corthésy J, Da Silva L, Migliavacca E, Tautvydaitė D, Oikonomidi A, Moullet B et al (2017) One-carbon metabolism, cognitive impairment and CSF measures of Alzheimer pathology: homocysteine and beyond. Alzheimers Res Ther 9(1):43

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Morrison LD, Smith DD, Kish SJ (1996) Brain S-adenosylmethionine levels are severely decreased in Alzheimer’s disease. J Neurochem 67(3):1328–1331

    Article  CAS  PubMed  Google Scholar 

  45. Sibani S, Melnyk S, Pogribny IP, Wang W, Hiou-Tim F, Deng L, Trasler J, James SJ et al (2002) Studies of methionine cycle intermediates (SAM, SAH), DNA methylation and the impact of folate deficiency on tumor numbers in Min mice. Carcinogenesis 23(1):61–65

    Article  CAS  PubMed  Google Scholar 

  46. Knock E, Deng L, Krupenko N, Mohan RD, Wu Q, Leclerc D, Gupta S, Elmore CL et al (2011) Susceptibility to intestinal tumorigenesis in folate-deficient mice may be influenced by variation in one-carbon metabolism and DNA repair. J Nutr Biochem 22(11):1022–1029

    Article  CAS  PubMed  Google Scholar 

  47. James SJ, Melnyk S, Pogribna M, Pogribny IP, Caudill MA (2002) Elevation in S-adenosylhomocysteine and DNA hypomethylation: potential epigenetic mechanism for homocysteine-related pathology. J Nutr 132(8):2361S–2366S

    Article  CAS  PubMed  Google Scholar 

  48. Fuso A, Nicolia V, Cavallaro RA, Scarpa S (2011) DNA methylase and demethylase activities are modulated by one-carbon metabolism in Alzheimer’s disease models. J Nutr Biochem 22(3):242–251

    Article  CAS  PubMed  Google Scholar 

  49. Fuso A, Nicolia V, Cavallaro RA, Ricceri L, D’anselmi F, Coluccia P, Calamandrei G, Scarpa S (2008) B-vitamin deprivation induces hyperhomocysteinemia and brain S-adenosylhomocysteine, depletes brain S-adenosylmethionine, and enhances PS1 and BACE expression and amyloid-β deposition in mice. Mol Cell Neurosci 37(4):731–746

    Article  CAS  PubMed  Google Scholar 

  50. Feng J, Zhou Y, Campbell SL, Le T, Li E, Sweatt JD, Silva AJ, Fan G (2010) Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat Neurosci 13(4):423–430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Morris MJ, Adachi M, Na ES, Monteggia LM (2014) Selective role for DNMT3a in learning and memory. Neurobiol Learn Mem 115:30–37

    Article  CAS  PubMed  Google Scholar 

  52. Shen W, Heeley JM, Carlston CM, Acuna-Hidalgo R, Nillesen WM, Dent KM, Douglas GV, Levine KL et al (2017) The spectrum of DNMT3A variants in Tatton–Brown–Rahman syndrome overlaps with that in hematologic malignancies. Am J Med Genet 173(11):3022–3028

    Article  CAS  PubMed  Google Scholar 

  53. Chouliaras L, Mastroeni D, Delvaux E, Grover A, Kenis G, Hof PR, Steinbusch HW, Coleman PD et al (2013) Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer’s disease patients. Neurobiol Aging 34(9):2091–2099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Volmar C-H, Wahlestedt C (2015) Histone deacetylases (HDACs) and brain function. Neuroepigenetics 1:20–27

    Article  Google Scholar 

  55. Akchiche N, Bossenmeyer-Pourié C, Kerek R, Martin N, Pourié G, Koziel V, Helle D, Alberto J-M et al (2012) Homocysteinylation of neuronal proteins contributes to folate deficiency-associated alterations of differentiation, vesicular transport, and plasticity in hippocampal neuronal cells. FASEB J 26(10):3980–3992

    Article  CAS  PubMed  Google Scholar 

  56. Agis-Balboa RC, Pavelka Z, Kerimoglu C, Fischer A (2013) Loss of HDAC5 impairs memory function: implications for Alzheimer’s disease. J Alzheimers Dis 33(1):35–44

    Article  CAS  PubMed  Google Scholar 

  57. Fuks F, Burgers WA, Brehm A, Hughes-Davies L, Kouzarides T (2000) DNA methyltransferase Dnmt1 associates with histone deacetylase activity. Nat Genet 24(1):88–91

    Article  CAS  PubMed  Google Scholar 

  58. Liu X, Luo M, Wu K (2012) Epigenetic interplay of histone modifications and DNA methylation mediated by HDA6. Plant Signal Behav 7(6):633–635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Bierer LM, Haroutunian V, Gabriel S, Knott PJ, Carlin LS, Purohit DP, Perl DP, Schmeidler J et al (1995) Neurochemical correlates of dementia severity in Alzheimer’s disease: relative importance of the cholinergic deficits. J Neurochem 64(2):749–760

    Article  CAS  PubMed  Google Scholar 

  60. Scherer EB, Loureiro SO, Vuaden FC, da Cunha AA, Schmitz F, Kolling J, Savio LEB, Bogo MR et al (2014) Mild hyperhomocysteinemia increases brain acetylcholinesterase and proinflammatory cytokine levels in different tissues. Mol Neurobiol 50(2):589–596

    Article  CAS  PubMed  Google Scholar 

  61. Hung S-Y, Fu W-M (2017) Drug candidates in clinical trials for Alzheimer’s disease. J Biomed Sci 24(1):47

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Colovic MB, Krstic DZ, Lazarevic-Pasti TD, Bondzic AM, Vasic VM (2013) Acetylcholinesterase inhibitors: pharmacology and toxicology. Curr Neuropharmacol 11(3):315–335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Whiley L, Sen A, Heaton J, Proitsi P, García-Gómez D, Leung R, Smith N, Thambisetty M et al (2014) Evidence of altered phosphatidylcholine metabolism in Alzheimer’s disease. Neurobiol Aging 35(2):271–278

    Article  CAS  PubMed  Google Scholar 

  64. Haughey NJ, Bandaru VV, Bae M, Mattson MP (2010) Roles for dysfunctional sphingolipid metabolism in Alzheimer’s disease neuropathogenesis. Biochim Biophys Acta 1801(8):878–886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Christensen KE, Wu Q, Wang X, Deng L, Caudill MA, Rozen R (2010) Steatosis in mice is associated with gender, folate intake, and expression of genes of one-carbon metabolism. J Nutr 140(10):1736–1741

    Article  CAS  PubMed  Google Scholar 

  66. Bahous RH, Jadavji NM, Deng L, Cosín-Tomás M, Lu J, Malysheva O, Leung K-Y, Ho M-K et al (2017) High dietary folate in pregnant mice leads to pseudo-MTHFR deficiency and altered methyl metabolism, with embryonic growth delay and short-term memory impairment in offspring. Hum Mol Genet 26(5):888–900

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Mattson MP, Shea TB (2003) Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders. Trends Neurosci 26(3):137–146

    Article  CAS  PubMed  Google Scholar 

  68. Bossy-Wetzel E, Schwarzenbacher R, Lipton SA (2004) Molecular pathways to neurodegeneration. Nat Med 10(7):S2–S9

    Article  PubMed  CAS  Google Scholar 

  69. Selhub J, Troen A, Rosenberg IH (2010) B vitamins and the aging brain. Nutr Rev 68(suppl_2):S112–S118

    Article  PubMed  Google Scholar 

  70. Hoffman A, Taleski G, Qian H, Wasek B, Arning E, Bottiglieri T, Sontag J-M, Sontag E (2018) Methylenetetrahydrofolate reductase deficiency deregulates regional brain amyloid-β protein precursor and phosphorylation levels. J Alzheimers Dis (Preprint) 1–15

  71. Fuso A, Ferraguti G, Scarpa S, Ferrer I, Lucarelli M (2015) Disclosing bias in bisulfite assay: MethPrimers underestimate high DNA methylation. PLoS One 10(2):e0118318

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Nagata T, Kobayashi N, Ishii J, Shinagawa S, Nakayama R, Shibata N, Kuerban B, Ohnuma T et al (2015) Association between DNA methylation of the BDNF promoter region and clinical presentation in Alzheimer’s disease. Dement Geriatr Cogn Dis Extra 5(1):64–73

    Article  PubMed  PubMed Central  Google Scholar 

  73. Zheng F, Zhou X, Moon C, Wang H (2012) Regulation of brain-derived neurotrophic factor expression in neurons. Int J Physiol Pathophysiol Pharmacol 4(4):188

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Lubin FD, Roth TL, Sweatt JD (2008) Epigenetic regulation of BDNF gene transcription in the consolidation of fear memory. J Neurosci 28(42):10576–10586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. McKinney BC, Lin C-W, Oh H, Tseng GC, Lewis DA, Sibille E (2015) Hypermethylation of BDNF and SST genes in the orbital frontal cortex of older individuals: a putative mechanism for declining gene expression with age. Neuropsychopharmacology 40(11):2604–2613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Iwata A, Nagata K, Hatsuta H, Takuma H, Bundo M, Iwamoto K, Tamaoka A, Murayama S et al (2013) Altered CpG methylation in sporadic Alzheimer’s disease is associated with APP and MAPT dysregulation. Hum Mol Genet 23(3):648–656

    Article  PubMed  CAS  Google Scholar 

  77. Eckart S, Hörtnagl H, Kronenberg G, Gertz K, Hörster H, Endres M, Hellweg R (2013) Reduced nerve growth factor levels in stress-related brain regions of folate-deficient mice. Neuroscience 245:129–135

    Article  CAS  PubMed  Google Scholar 

  78. Poo M-M (2001) Neurotrophins as synaptic modulators. Nat Rev Neurosci 2(1):24

    Article  CAS  PubMed  Google Scholar 

  79. Choi Y, Lee K, Ryu J, Kim HG, Jeong AY, Woo R-S, Lee J-H, Hyun JW et al (2014) Neuritin attenuates cognitive function impairments in Tg2576 Mouse Model of Alzheimer’s disease. PLoS One 9(8):e104121

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Troen AM, Shea-Budgell M, Shukitt-Hale B, Smith DE, Selhub J, Rosenberg IH (2008) B-vitamin deficiency causes hyperhomocysteinemia and vascular cognitive impairment in mice. Proc Natl Acad Sci U S A 105(34):12474–12479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Pourié G, Martin N, Bossenmeyer-Pourié C, Akchiche N, Guéant-Rodriguez RM, Geoffroy A, Jeannesson E, Chehadeh SEH et al (2015) Folate-and vitamin B12-deficient diet during gestation and lactation alters cerebellar synapsin expression via impaired influence of estrogen nuclear receptor α. FASEB J 29(9):3713–3725

    Article  PubMed  CAS  Google Scholar 

  82. Craciunescu CN, Brown EC, Mar M-H, Albright CD, Nadeau MR, Zeisel SH (2004) Folic acid deficiency during late gestation decreases progenitor cell proliferation and increases apoptosis in fetal mouse brain. J Nutr 134(1):162–166

    Article  CAS  PubMed  Google Scholar 

  83. Werstuck GH, Lentz SR, Dayal S, Hossain GS, Sood SK, Shi YY, Zhou J, Maeda N et al (2001) Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. J Clin Invest 107(10):1263–1273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Sudduth TL, Powell DK, Smith CD, Greenstein A, Wilcock DM (2013) Induction of hyperhomocysteinemia models vascular dementia by induction of cerebral microhemorrhages and neuroinflammation. J Cereb Blood Flow Metab 33(5):708–715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Poirel O, Mella S, Videau C, Ramet L, Davoli MA, Herzog E, Katsel P, Mechawar N et al (2018) Moderate decline in select synaptic markers in the prefrontal cortex (BA9) of patients with Alzheimer’s disease at various cognitive stages. Sci Rep 8(1):938

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Drachman DA (2006) Aging of the brain, entropy, and Alzheimer disease. Neurology 67(8):1340–1352

    Article  CAS  PubMed  Google Scholar 

  87. Crawley JN (2007) What’s wrong with my mouse? Behavioural phenotyping of transgenic and knockout mice, 2nd edn. John Wiley& Sons, Inc, New Jersey

    Book  Google Scholar 

  88. Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3(7):research0034

    Article  PubMed  PubMed Central  Google Scholar 

  89. Leclerc D, Cao Y, Deng L, Mikael LG, Wu Q, Rozen R (2013) Differential gene expression and methylation in the retinoid/PPARA pathway and of tumor suppressors may modify intestinal tumorigenesis induced by low folate in mice. Mol Nutr Food Res 57(4):686–697

    Article  CAS  PubMed  Google Scholar 

  90. Luttropp K, Sjöholm LK, Ekström TJ (2015) Global analysis of DNA 5-methylcytosine using the luminometric methylation assay, LUMA. Methods Mol Biol 1315:209–219

    Article  PubMed  Google Scholar 

  91. Christensen KE, Mikael LG, Leung KY, Levesque N, Deng L, Wu Q, Malysheva OV, Best A et al (2015) High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice. Am J Clin Nutr 101(3):646–658. https://doi.org/10.3945/ajcn.114.086603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Yan J, Jiang X, West AA, Perry CA, Malysheva OV, Devapatla S, Pressman E, Vermeylen F et al (2012) Maternal choline intake modulates maternal and fetal biomarkers of choline metabolism in humans. Am J Clin Nutr 95(5):1060–1071

    Article  CAS  PubMed  Google Scholar 

  93. Holm PI, Ueland PM, Kvalheim G, Lien EA (2003) Determination of choline, betaine, and dimethylglycine in plasma by a high-throughput method based on normal-phase chromatography-tandem mass spectrometry. Clin Chem 49(2):286–294

    Article  CAS  PubMed  Google Scholar 

  94. Koc H, Mar MH, Ranasinghe A, Swenberg JA, Zeisel SH (2002) Quantitation of choline and its metabolites in tissues and foods by liquid chromatography/electrospray ionization-isotope dilution mass spectrometry. Anal Chem 74(18):4734–4740

    Article  CAS  PubMed  Google Scholar 

  95. Kim JK, Harada K, Bamba T, Fukusaki E, Kobayashi A (2005) Stable isotope dilution-based accurate comparative quantification of nitrogen-containing metabolites in Arabidopsis thaliana T87 cells using in vivo (15)N-isotope enrichment. Biosci Biotechnol Biochem 69(7):1331–1340

    Article  CAS  PubMed  Google Scholar 

  96. Jadavji NM, Bahous RH, Deng L, Malysheva O, Grand’maison M, Bedell BJ, Caudill MA, Rozen R (2014) Mouse model for deficiency of methionine synthase reductase exhibits short-term memory impairment and disturbances in brain choline metabolism. Biochem J 461(2):205–212. https://doi.org/10.1042/BJ20131568

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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

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.

Author information

Author notes

  1. Renata H. Bahous and Marta Cosín-Tomás contributed equally to this work.

Authors and Affiliations

  1. Departments of Human Genetics and Pediatrics, Research Institute of the McGill University Health Centre, 1001 Décarie Boulevard, Room EM0.3211, Montreal, Quebec, H4A 3J1, Canada

    Renata H. Bahous, Marta Cosín-Tomás, Liyuan Deng, Daniel Leclerc & Rima Rozen

  2. Division of Nutritional Sciences and Genomics, Cornell University, Ithaca, NY, USA

    Olga Malysheva & Marie A. Caudill

  3. Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada

    Ming-Kai Ho & Barry J. Bedell

  4. Pharmacology Unit, Faculty of Pharmacy, Institut de Neurociència Universitat de Barcelona (IBUB), Nucli Universitari de Pedralbes, Barcelona, Spain

    Mercè Pallàs

  5. Institute of Biomedical Investigation of Barcelona, Spanish National Research Council, Barcelona, Spain

    Perla Kaliman

Authors
  1. Renata H. Bahous
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marta Cosín-Tomás
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liyuan Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Daniel Leclerc
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Olga Malysheva
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ming-Kai Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mercè Pallàs
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Perla Kaliman
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Barry J. Bedell
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Marie A. Caudill
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Rima Rozen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rima Rozen.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Electronic Supplementary Material

ESM 1

(DOCX 150 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bahous, R.H., Cosín-Tomás, M., Deng, L. et al. Early Manifestations of Brain Aging in Mice Due to Low Dietary Folate and Mild MTHFR Deficiency. Mol Neurobiol 56, 4175–4191 (2019). https://doi.org/10.1007/s12035-018-1375-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-018-1375-3

Keywords

Search

Navigation