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

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 B 6 (0.01 mg/kg), and B 12 (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 4 th 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 B 6 /B 12 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.

Decreased Netrin-1 in Mild Cognitive Impairment and Alzheimer’s Disease Patients

“…Furthermore, exogenous application of netrin-1 has been found to regulate Aβ peptide production, oligomerization and clearance in AD models, to improve cognitive dysfunction as assessed in the novel object recognition task and ameliorate impaired spatial memory as demonstrated in the morris water maze test (Lourenço et al, 2009;Spilman et al, 2016;Shabani et al, 2017;Zamani et al, 2019). Previous data also indicates that down-regulation of netrin-1 attribute to hyper-methylation of its gene can result in memory loss (Kalani et al, 2019). In addition, netrin-1 protected Aβ1-42-exposed SH-SY5Y cells through NF-κB/Nrf2 dependent mechanism (Zamani et al, 2020).…”

mTOR Complex 1 Content and Regulation Is Adapted to Animal Longevity

“…Evidence suggests that Met promotes neuroinflammation and impairs neurogenesis [ 91 ]. Met is also associated with memory loss [ 92 ], due to the alteration of methylation patterns, and thus the expression of Netrin-1, which is involved in neuronal processes. Since Netrin-1 inhibits mTORC1 [ 93 ], these results suggest that memory impairment in AD might be associated with hyperactivation of mTORC.…”

The role of wheat embryo globulin nutrients in improving cognitive dysfunction in AD rats

“…WEGN can aid in biological processes, such as improving cognitive function, strengthening immunity, and remodeling the gut microbiota. [26][27][28][29][30] Previous studies have shown that WEGN aids in antioxidation, maintaining the choline balance, reducing neuronal damage, and restoring the memory impairment of AD model rats induced by D-gal combined with AlCl 3 . 31 Despite the beneficial pharmacological effects of the WEGN, its mechanism in relieving AD is unclear.…”