Advertisement

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 Tyagi
Original Article

Abstract

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.

Keywords

Homocysteine Neuronal dysfunction Cerebrovascular damage Blood-brain barrier Cognitive dysfunction 

Notes

Acknowledgments

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

References

  1. Basati G, Razavi AE, Abdi S, Sarrafzedegan N (2014) Association of plasma leptin, homocysteine and nitric oxide levels with the presence and unstability of coronary artery disease. Biomark Med 8:405–412CrossRefPubMedGoogle Scholar
  2. Chaturvedi P, Kamat PK, Kalani A, Familtseva A, Tyagi SC (2016) High methionine diet poses cardiac threat: a molecular insight. J Cell Physiol 231:1554–1561CrossRefPubMedGoogle Scholar
  3. Cheng J, Kaplowitz N (2004) Hyperhomocysteinemia, endoplasmic reticulum stress, and alcoholic injury. World J Gastroenterol 10:1699–1708CrossRefGoogle Scholar
  4. Chow K, Cheung F, Lao TT, O K (1999) Effect of homocysteine on the production of nitric oxide in endothelial cells. Clin Exp Pharmacol Physiol 26:817–818Google Scholar
  5. Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM (1998) Folate, vitaminB12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 55:1449–1455CrossRefPubMedGoogle Scholar
  6. FAO/WHO (1973) "Energy and Protein Requirements." Report of a Joint FAO/WHO Ad Hoc Expert Committee Technical Report Series No. 552; FAO Nutrition Meetings Report Series 52. http://apps.who.int/iris/bitstream/10665/41042/1/WHO_TRS_522_eng.pdf
  7. Förstermann U, Sessa WC (2012) Nitric oxide synthases: regulation and function. Eur Heart J 33:829–837CrossRefPubMedGoogle Scholar
  8. Ganguly P, Alam SF (2015) Role of homocysteine in the development of cardiovascular disease. Nutr J 14:6CrossRefPubMedPubMedCentralGoogle Scholar
  9. Gomez J, Caro P, Sanchez I, Naudi A, Jove M, Portero-Otin M, Lopez-Torres M, Pamplona R, Barja G (2009) Effect of methionine dietary supplementation on mitochondrial oxygen radical generation and oxidative DNAdamage in ratliver and heart. J Bioenerg Biomembr 41:309–321CrossRefPubMedGoogle Scholar
  10. Hainsworth AH, Yeo NE, Weekman EM, Wilcock DM (2016) Homocysteine, hyperhomocysteinemia and vascular contributions to cognitive impairment and dementia (VCID). Biochim Biophys Acta 1862:1008–1017CrossRefPubMedGoogle Scholar
  11. Hankey GJ, Eikelboom JW (2001) Homocysteine and stroke. Curr Opin Neurol 14:95–102CrossRefPubMedGoogle Scholar
  12. Harper AE, Benevenga NJ, Wohlhueter RM (1970) Effects of ingestion of disproportionate amounts of amino acids. Physiol Rev 50:428–558CrossRefPubMedGoogle Scholar
  13. Irwin MI, Hegsted DM (1971) A conspectus of research on amino acid requirements of man. J Nutr 101:539–566CrossRefPubMedGoogle Scholar
  14. Jacobsen DW (2000) Hyperhomocysteinemia and oxidative stress: time for a reality check? Arterioscler Thromb Vasc Biol 20:1182–1184CrossRefPubMedGoogle Scholar
  15. Kalani A, Kamat PK, Familtseva A, Chaturvedi P, Muradashvili N, Narayanan N, Tyagi SC, Tyagi N (2014) Role of microRNA29b in blood-brain barrier dysfunction during hyperhomocysteinemia: an epigenetic mechanism. J Cereb Blood Flow Metab 34:1212–1222CrossRefPubMedPubMedCentralGoogle Scholar
  16. Kalani A, Kamat PK, Tyagi N (2015) Diabetic stroke severity: epigenetic remodeling and neuronal, glial, and vascular dysfunction. Diabetes 64:4260–4271CrossRefPubMedPubMedCentralGoogle Scholar
  17. Kalani A, Pushpakumar SB, Vacek JC, Tyagi SC, Tyagi N (2016) Inhibition of MMP-9 attenuates hypertensive cerebrovascular dysfunction in Dahl salt-sensitive rats. Mol Cell Biochem 413:25–35CrossRefPubMedPubMedCentralGoogle Scholar
  18. Kamat PK, Kalani A, Givvimani S, Sathnur PB, Tyagi SC, Tyagi N (2013) Hydrogensulfideattenuatesneurodegeneration and neurovasculardysfunctioninduced by intracerebral-administered homocysteine in mice. Neuroscience 252:302–319CrossRefPubMedPubMedCentralGoogle Scholar
  19. Kamath AF, Chauhan AK, Kisucka J, Dole VS, Loscalzo J, Handy DE, Wagner DD (2006) Elevated levels of homocysteine compromise blood-brain barrier integrity in mice. Blood 107:591–593CrossRefPubMedPubMedCentralGoogle Scholar
  20. Koladiya RU, Jaggi AS, Singh N, Sharma BK (2008) Ameliorative role of atorvastatin and Pitavastatin in L-methionine induced vascular dementia in rats. BMC Pharmacol 8:14.  https://doi.org/10.1186/1471-2210-8-14 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Leger M, Quiedeville A, Bouet V, Haelewyn B, Boulouard M, Schumann-Bard P, Freret T (2013) Object recognition test in mice. Nat Protoc 8:2531–2537CrossRefPubMedGoogle Scholar
  22. Lominadze D, Roberts AM, Tyagi N, Moshal KS, Tyagi SC (2006) Homocysteine causes cerebrovascular leakage in mice. Am J Physiol Heart Circ Physiol 290:H1206–H1213CrossRefPubMedGoogle Scholar
  23. Lu K, Xu X, Cui S, Wang F, Zhang B, Zhao Y (2015) Serum neuron specific enolase level as a predictor of prognosis in acute ischemic stroke patients after intravenous thrombolysis. J Neurol Sci 359:202–206CrossRefPubMedGoogle Scholar
  24. Lueptow LM (2017) Novel object recognition test for the investigation of learning and memory in mice. J Vis Exp 126.  https://doi.org/10.3791/55718
  25. Mattson MP, Shea TB (2003) Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders. Trends Neurosci 26:137–146CrossRefPubMedGoogle Scholar
  26. Miller JW (1999) Homocysteine and Alzheimer's disease. Nutr Rev 57:126–129PubMedGoogle Scholar
  27. Miller AL (2003) The methionine-homocysteine cycle and its effects on cognitive diseases. Altern Med Rev 8:7–19PubMedGoogle Scholar
  28. Millward J (1990) Amino acid requirements in adult man. Am J Clin Nutr 51:492–496CrossRefPubMedGoogle Scholar
  29. Mori N, Hirayama K (2000) Long-term consumption of a methionine-supplemented diet increases iron and lipid peroxide levels in rat liver. J Nutr 130:2349–2355CrossRefPubMedGoogle Scholar
  30. Muradashvili N, Tyagi R, Metreveli N, Tyagi SC, Lominadze D (2014) Ablation of MMP9 gene ameliorates paracellular permeability and fibrinogen-amyloid beta complex formation during hyperhomocysteinemia. J Cereb Blood Flow Metab 34:1472–1482CrossRefPubMedPubMedCentralGoogle Scholar
  31. Obeid R, Herrmann W (2006) Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia. FEBS Lett 580:2994–3005CrossRefPubMedGoogle Scholar
  32. O'Dell TJ, Hawkins RD, Kandel ER, Arancio O (1991) Tests of the roles of two diffusible substances in long-term potentiation: evidence for nitric oxide as a possible early retrograde messenger. Proc Natl Acad Sci U S A 88:11285–11289CrossRefPubMedPubMedCentralGoogle Scholar
  33. Oldendorf WH, Szabo J (1976) Amino acid assignment to one of three blood-brain barrier amino acid carriers. Am J Phys 230:94–98Google Scholar
  34. Sabour H, Nazari M, Latifi S, Soltani Z, Shakeri H, Larijani B, Ghodsi SM, Razavi SHE (2016) The relationship between dietary intakes of amino acids and bone mineral density among individuals with spinal cord injury. Oman Med J 31:22–28CrossRefPubMedPubMedCentralGoogle Scholar
  35. Schmued LC, Stowers CC, Scallet AC, Xu L (2005) Fluoro-jade C results in ultra high resolution and contrast labeling of degenerating neurons. Brain Res 1035:24–31CrossRefPubMedGoogle Scholar
  36. Shen Y, Gao HM (2015) Serum somatostatin and neuron-specific enolase might be biochemical markers of vascular dementia in the early stage. Int J Clin Exp Med 8:19471–19475PubMedPubMedCentralGoogle Scholar
  37. Siri PW, Verhoef P, Kok FJ (1998) Vitamins B6, B12, and folate: association with plasma total homocysteine and risk of coronary atherosclerosis. J Am Coll Nutr 17:435–441CrossRefPubMedGoogle Scholar
  38. Smith AD (2008) The worldwide challenge of the dementias: a role for B vitamins and homocysteine? Food Nutr Bull 29:S143–S172CrossRefPubMedGoogle Scholar
  39. Troen AM, French EE, Roberts JF, Selhub J, Ordovas JM, Parnell LD, Lai CQ (2007) Lifespan modification by glucose and methionine in Drosophila melanogaster fed a chemically defined diet. Age (Dordr) 29:29–39CrossRefGoogle Scholar
  40. Tyagi N, Sedoris KC, Steed M, Ovechkin AV, Moshal KS, Tyagi SC (2005) Mechanisms of homocysteine-induced oxidative stress. Am J Physiol Heart Circ Physiol 289:H2649–H2656CrossRefPubMedGoogle Scholar
  41. Upchurch GR Jr, Welch GN, Fabian AJ, Pigazzi A, Keaney JF Jr, Loscalzo J (1997) Stimulation of endothelial nitric oxide production by homocyst(e)ine. Atherosclerosis 132:177–185CrossRefPubMedGoogle Scholar
  42. Wang G, Woo CW, Sung FL, Siow YL O K(2002) Increased monocyte adhesion to aortic endothelium in rats with hyperhomocysteinemia: role of chemokine and adhesion molecules. Arterioscler Thromb Vasc Biol 22:1777–1783CrossRefPubMedGoogle Scholar
  43. Yang AN, Zhang HP, Sun Y, Yang XL, Wang N, Zhu G, Zhang H, Xu H, Ma SC, Zhang Y, Li GZ, Jia YX, Cao J, Jiang YD (2015) High-methionine diet accelerate atherosclerosis by HHcy-mediatedFABP4genedemethylationpathwayviaDNMT1 in ApoE(−/−) mice. FEBS Lett 589:3998–4009CrossRefPubMedGoogle Scholar
  44. Young SN, Shalchi M (2005) The effect of methionine and S-adenosylmethionine on S-adenosylmethionine levels in the rat brain. J Psychiatry Neurosci 30:44–48PubMedPubMedCentralGoogle Scholar
  45. Zhang X, Li H, Jin H, Ebin Z, Brodsky S, Goligorsky MS (2000) Effects of homocysteine on endothelial nitric oxide production. Am J Physiol Renal Physiol 279:F671–F678CrossRefPubMedGoogle Scholar
  46. Zhang JW, Yan R, Tang YS, Guo YZ, Chang Y, Jing L, Wang YL, Zhang JZ (2017) Hyperhomocysteinemia-induced autophagy and apoptosis with downregulation of hairy enhancer of split 1/5 in cortical neurons in mice. Int J Immunopathol Pharmacol 30:371–382CrossRefPubMedPubMedCentralGoogle Scholar
  47. Zhuo JM, Portugal GS, Kruger WD, Wang H, Gould TJ, Pratico D (2010) Diet-induced hyperhomocysteinemia increases amyloid-beta formation and deposition in a mouse model of Alzheimer's disease. Curr Alzheimer Res 7:140–149CrossRefPubMedPubMedCentralGoogle Scholar

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
  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

Personalised recommendations