Metabolic Brain Disease

, Volume 33, Issue 6, pp 1923–1934 | Cite as

High methionine, low folate and low vitamin B6/B12 (HM-LF-LV) diet causes neurodegeneration and subsequent short-term memory loss

  • Mohammed Nuru
  • Nino Muradashvili
  • Anuradha Kalani
  • David Lominadze
  • Neetu TyagiEmail author
Original Article


Methionine is an essential amino acid found in rich quantities in average American diet such as meats, fish and eggs. Excessive consumption of such food often exceeds the normal requirement of the methionine in our body; which found to be related to the development of neurodegenerative disorders. However, the mechanistic pathways of methionine’s influence on the brain are unclear. The present study is focus on the effects of high methionine, low folate and low vitamin B6/B12 (HM-LF-LV) diet on the dysfunction of neuronal and vascular specific markers in the brain. C57BL6/J male mice (8–10 week old) were fed with HM-LF-LV diet for a 6 week period. Cognitive function of mice was determine by measuring short-term memory using a Novel Object Recognition test (NORT). Neuronal dysfunction were evaluate by measuring the levels of Neuronal nuclear antigen (NeuN), Neuron-specific-enolase (NSE) and Fluoro-jade C(FJC) fluorescence; while cerebrovascular disruption were evaluate by assessing levels of endothelial junction proteins Vascular Endothelial-Cadherin (VE-Cadherin) and Claudin-5 in harvested brain tissue. Cerebrovascular permeability was assess by evaluating microvascular leakage of fluorescently labeled albumin in vivo. Endothelial and Neuronal Nitric Oxide Synthase (eNOS, nNOS) regulation and vascular inflammation (ICAM: intercellular adhesion molecules) were also evaluate in brain tissue. All assessments were conduct at weekly intervals throughout the study duration. NORT showed a significant temporal decrease in short-term memory of mice fed on HM-LF-LV diet for 6 weeks compared to the wild-type control group. Our experimental data showed that neuronal dysfunction (decreased NeuN levels and increased FJC positive neurons in brain) was more prominent in HM-LF-LV diet fed mice compared to normal diet fed control mice. In experimental mice, cerebrovascular disruption was found to be elevated as evident from increased pial venular permeability (microvascular leakage) and decreased in VE-Cadherin expression compared to control. Slight decrease in nNOS and increase in eNOS in experimental mice suggest a trend towards the decrease in potential for neuronal development due to the long-term HM-LF-LV diet fed. Collectively, our results suggest that a diet containing high methionine, low folate and low vitamin B6/B12 results in increased neuronal degeneration and vascular dysfunction, leading to short-term memory loss. Interestingly, significant neuronal damage precedes vascular dysfunction.


Homocysteine Neuronal dysfunction Cerebrovascular damage Blood-brain barrier Cognitive dysfunction 



NIH (National Institute of Health) Grant HL-107640 and AR-067667 to NT and NS-084823 to DL supported this study.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Mohammed Nuru
    • 1
  • Nino Muradashvili
    • 1
  • Anuradha Kalani
    • 2
  • David Lominadze
    • 1
  • Neetu Tyagi
    • 1
    • 3
    Email author
  1. 1.Department of PhysiologyUniversity of Louisville School of MedicineLouisvilleUSA
  2. 2.Department of CardiologyUniversity of Louisville School of MedicineLouisvilleUSA
  3. 3.Department of Physiology, Health Science Center, A-1201University of LouisvilleLouisvilleUSA

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