Neural Regeneration Research ›› 2019, Vol. 14 ›› Issue (7): 1247-1254.doi: 10.4103/1673-5374.251333

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A high methionine, low folate and vitamin B6/B12 containing diet can be associated with memory loss by epigenetic silencing of netrin-1

Anuradha Kalani 1 , Pankaj Chaturvedi 1 , Komal Kalani 2, 3 , Pradip K. Kamat 1 , Poonam Chaturvedi 4 , Neetu Tyagi 1   

  1. 1 Department of Physiology, School of Medicine, University of Louisville, Louisville, KY, USA
    2 Medicinal Chemistry Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, India
    3 Pharmacology Department and Toxicology, Higuchi Biosciences Center, University of Kansas, Lawrence, KS, USA
    4 Department of Neurology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, India
  • Online:2019-07-15 Published:2019-07-15
  • Contact: Anuradha Kalani, MS, PhD, anukalani@gmail.com; a0kala02@exchange.louisville.edu; Pankaj Chaturvedi, PhD, pcjuly4@gmail.com.
  • Supported by:

    Part of this study was supported by NIH grant HL-107640 (to NT).

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Abstract:

Memory-epigenetics which is the loss of memory due to epigenetic modifications can be due to the silencing of genes involved in cognitive functions and this is the basis of the current study. We hypothesize that a diet containing high methionine and low vitamins can lead to memory impairment by increasing global DNA methylation and therefore, silencing the netrin-1 gene, which encodes the glycoprotein involved in neurogenesis, axonal guidance and maintenance of the synaptic plasticity. Wild type (C57BL/6J) mice were fed with a diet containing excess methionine (1.2%), low-folate (0.08 mg/kg), vitamin B6 (0.01 mg/kg), and B12 (10.4 mg/kg) for 6 weeks. Mice were examined weekly for the long-term memory function, using a passive avoidance test, which determined loss of fear-motivated long-term memory starting from the fourth week of diet. Similarly, an increase in brain %5-methyl cytosine was observed starting from the 4th week of diet in mice. Mice fed with a high methionine, low folate and vitamins containing diet showed a decrease in netrin-1 protein expression and an increase in netrin-1 gene promotor methylation, as determined by methylation-sensitive restriction enzyme-polymerase chain reaction analysis. The increase in methylation of netrin-1 gene was validated by high-resolution melting and sequencing analysis. Furthermore, the association of netrin-1 with memory was established by administering netrin that considerably restored long-term fear motivated memory. Taken together, these results suggest that a diet rich in methionine and lacking in folate and vitamin B6/B12 can induce defects in learning and memory. Furthermore, the data indicates that decrease in netrin-1 expression due to hyper-methylation of its gene can be associated with memory loss. The animal procedures were approved by the Institutional Animal Care and Use Committee, University of Louisville, USA (No. A3586-01) on February 2, 2018.

Key words: Alzheimer’s disease, epigenetics, memory, methionine, 5-methylcytosine, methylation, netrin-1