Neurocognitive Decline Caused by L-Methionine: A Mouse Model of Neurodegeneration

Yıl 2020, Cilt: 10 Sayı: 2, 59 - 66, 26.08.2020

Yağız M. Altun Erdem Tüzün Mark F. Mehler Şölen Gökhan

https://doi.org/10.26650/experimed.2020.0026

Öz

Objective: Neurodegenerative diseases are defined by irreversible neuronal and glial loss in the central nervous system. Despite sharing neural cell loss as a common denominator, they differ in their clinical manifestations in many aspects. We aimed to analyze the behavioral changes and underlying immunohistochemical changes in mice caused by an environmental stressor, l-methionine, to assess the spectrum of clinical findings observed in these diseases.
Material and Method: In this study, the mice are divided into 4 groups: female-control (n=13), female-methionine (n=12), male-control (n=12), male-methionine (n=13) to perform immunohistochemical and behavioral tests. Starting from post-natal week 6, the mice were either administered water or 8.2g/kg l-methionine for 12 weeks. Consequently, they underwent a series of behavioral tests to assess anxiety, depression, memory/learning, and motor functions. We performed immunohistochemical analysis on mice (3 randomly chosen mice from each group prior to behavior tests) which did not undergo behavioral tests.
Results: Compared to the control group, mice who received l-methionine were found to have significant hippocampus dependent spatial memory deficits. No significant differences were found in regards to anxiety and depression. Our immunohistochemical analysis showed a significantly increased senescent astrocyte to all astrocyte ratio in dentate gyrus of hippocampal formation.
Conclusion: Chronic administration of an oral high dose of l-methionine results in hippocampus dependent memory decline in mice. Parallel to this finding, the ratio of senescent astrocytes to all astrocytes increased in dentate gyrus.

Anahtar Kelimeler

L-methionine, cognitive decline, cellular senescence

Destekleyen Kurum

Research reported in the present work was supported by the National Institutes of Health

Proje Numarası

National Institute of Neurological Disorders and Stroke Grant RO1NS073758

L-Metiyoninin Neden Olduğu Nörokognitif Yıkılma: Bir Nörodejenerasyon Fare Modeli

Öz

Amaç: Nörodejeneratif hastalıklar geri dönüşü olmayan nöronal ve glial kayıplarla seyreden merkezi sinir sistemi yıkılımıdır. Bu hastalıklar her ne kadar nöral hücre yıkım ortak paydasında birleşseler de her biri farklı klinik bulgularla seyretmektedir. Bu hastalıklarda izlenen klinik tablo spektrumunu inceleyebilmek adına çevresel stresör olarak verilen l-metiyonin yüklemesinin yol açtığı davranış değişikliklerinin ve bu davranış değişikliklerinin temelinde olan immünohistokimyasal değişimlerin incelenmesi amaçlanmıştır.
Gereç ve Yöntem: Bu çalışmada davranış ve immünohistokimya testleri için fareler 4 gruba ayrılmıştır: dişi-kontrol (n=13), dişi-metiyonin (n=12), erkek-kontrol (n=12), erkek-metiyonin (n=13). Kontrol ve deney gruplarına post-natal 6. haftadan başlayarak, 12 hafta boyunca su veya 8.2 g/kg doza ulaşacak şekilde l-metiyoninli su verilmiştir. Bu sürenin sonunda farelere anksiyete, depresyon, hafıza/öğrenme ve motor fonksiyon testleri uygulanmıştır. Davranış testlerinde kullanmadığımız farelerin (her gruptan davranış testleri öncesi rastgele seçilmiş 3 fare) beyin kesitlerinde immünohistokimyasal analizler yapılmıştır.
Bulgular: L-metiyonin alan farelerde almayanlara kıyasla hipokampüs bağımlı mekansal hafızada istatistiksel olarak anlamlı bir fark görülmüştür. Depresyon ve anksiyete adına herhangi bir fark bulunmamıştır. Hipokampüs formasyonunun dentat girusunda yaptığımız immünohistokimyasal incelemede, hem dişi hem de erkek farelerde senesan astrositlerin tüm astrositlere olan oranı arasında istatistiksel olarak anlamlı bir fark saptanmamıştır.
Sonuç: Kronik yüksek doz oral l-metiyonin alımı farelerde anlamlı hipokampüs bağımlı mekansal hafıza bozukluklarına yol açmıştır. Buna paralel olarak, dentat girusta senesan astrositlerin tüm astrositlere oranı da artmıştır.

Anahtar Kelimeler

L-metiyonin, kognitif yıkım, hücresel senesans

Proje Numarası

National Institute of Neurological Disorders and Stroke Grant RO1NS073758

Kaynakça

• 1. Kovacs GG. Concepts and classification of neurodegenerative diseases. Handb Clin Neurol 2017; 145: 301-7. [CrossRef]
• 2. Molero, AE, Gokhan S, Gonzalez S, Feig JL, Alexandre LC, Mehler MF. Impairment of developmental stem cell-mediated striatal neurogenesis and pluripotency genes in a knock-in model of Huntington's disease. Proc Natl Acad Sci U S A 2009; 106: 21900-5. [CrossRef]
• 3. Hardiman O, Al-Chalabi A, Chio A, Corr EM, Logroscino G, Robberecht W, et al. Amyotrophic lateral sclerosis. Nature Reviews Disease Primers 2017; 3: 17071. [CrossRef]
• 4. DeTure MA, Dickson DW. The neuropathological diagnosis of Alzheimer's disease. Mol Neurodegener 2019; 14: 32. [CrossRef]
• 5. Gelders G, Baekelandt V, Van der Perren A. Linking neuroinflammation and neurodegeneration in parkinson's disease. Journal of İmmunology Research 2018; 4784268. [CrossRef]
• 6. Braak H, Del Tredici K, Schultz C, Braak E. Vulnerability of select neuronal types to Alzheimer's disease. Ann N Y Acad Sci 2000; 924: 53-61. [CrossRef]
• 7. Whitehouse PJ, Price DL, Clark AW, Coyle JT, DeLong MR. Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann Neurol 1981; 10: 122-6. [CrossRef]
• 8. Dickson DW. Parkinson's disease and parkinsonism: neuropathology. Cold Spring Harb Perspect Med 2012; 2. [CrossRef]
• 9. Sapp E, Schwarz C, Chase K, Bhide PG, Young AB, Penney J, Vonsattel JP, Aronin N, DiFiglia M. Huntingtin localization in brains of normal and Huntington's disease patients. Ann Neurol 1997; 42: 604-12. [CrossRef]
• 10. Pérez Ortiz JM, Orr HT. Spinocerebellar Ataxia Type 1: Molecular Mechanisms of Neurodegeneration and Preclinical Studies. Adv Exp Med Biol 2018; 1049: 135-45. [CrossRef]
• 11. Mehler MF, Gokhan S. Mechanisms underlying neural cell death in neurodegenerative diseases: alterations of a developmentally-mediated cellular rheostat. Trends Neurosci 2000; 23: 599-605. [CrossRef]
• 12. Mehler MF, Gokhan S. Developmental mechanisms in the pathogenesis of neurodegenerative diseases. Prog Neurobiol 2001; 63: 337-63. [CrossRef]
• 13. Armstrong RA. Risk factors for Alzheimer's disease. Folia Neuropathologica 2019; 57: 87-105. [CrossRef]
• 14. Illes J. Neurolinguistic features of spontaneous language production dissociate three forms of neurodegenerative disease: Alzheimer's, Huntington's, and Parkinson's. Brain Lang 1989; 37: 628-42. [CrossRef]
• 15. Brian C, Dalla Torre C, Citton V, Manara R, Pompanin S, Binotto G, et al. Cobalamin deficiency: clinical picture and radiological findings. Nutrients 2013; 5: 4521-39. [CrossRef]
• 16. Hrnčić D, Rašić-Marković A, Stojković T, Velimirović M, Puškaš N, Obrenović R et al. Hyperhomocysteinemia induced by methionine dietary nutritional overload modulates acetylcholinesterase activity in the rat brain. Mol Cell Biochem 2014; 396: 99-105. [CrossRef]
• 17. Tapia-Rojas C, Lindsay CB, Montecinos-Oliva C, Arrazola MS, Retamales RM, Bunout D et al. Is L-methionine a trigger factor for Alzheimer's-like neurodegeneration?: Changes in Aβ oligomers, tau phosphorylation, synaptic proteins, Wnt signaling and behavioral impairment in wild-type mice. Molecular neurodegeneration 2015; 10: 62. [CrossRef]
• 18. Durand P, Prost M, Loreau N, Lussier-Cacan S, Blache D. Impaired Homocysteine Metabolism and Atherothrombotic Disease. Laboratory Investigation 2001; 81: 645-72. [CrossRef]
• 19. Bath PM, Appleton JP, Sprigg N, The Insulin Resistance Intervention after Stroke trial: A perspective on future practice and research. International Journal of Stroke 2016; 11: 741-43. [CrossRef]
• 20. Yoshitomi R, Nakayama K, Yamashita S, Kumazoe M, Lin T-A, Mei C-Y et al. Plasma Homocysteine Concentration is Associated with the Expression Level of Folate Receptor 3. Scientific reports 2020; 10: 10283. [CrossRef]
• 21. Schöneich C. Methionine oxidation by reactive oxygen species: reaction mechanisms and relevance to Alzheimer's disease. Biochim Biophys Acta 2005; 1703: 111-9. [CrossRef]
• 22. Li Y, Huang T, Zheng Y, Muka T, Troup J, Hu FB. Folic Acid Supplementation and the Risk of Cardiovascular Diseases: A Meta-Analysis of Randomized Controlled Trials. J Am Heart Assoc 2016; 5. [CrossRef]
• 23. Debacq-Chainiaux F, Erusalimsky JD, Campisi J, Toussaint O. Protocols to detect senescence-associated beta-galactosidase (SAβgal) activity, a biomarker of senescent cells in culture and in vivo. Nature Protocols 2009; 4: 1798-806. [CrossRef]
• 24. Tomé WA, Gökhan Ş, Brodin NP, Gulinello ME, Heard J, Mehler MF, et al. A mouse model replicating hippocampal sparing cranial irradiation in humans: A tool for identifying new strategies to limit neurocognitive decline. Sci Rep 2015; 5: 14384. [CrossRef]
• 25. Quéré I, Hillaire-Buys D, Brunschwig C, Chapal J, Janbon C, Blayac JP, et al. Effects of homocysteine on acetylcholine- and adenosine-induced vasodilatation of pancreatic vascular bed in rats. British journal of pharmacology 1997; 122: 351-7. [CrossRef]
• 26. Montalescot G. Homocysteine: the new player in the field of coronary risk. Heart (British Cardiac Society) 1996; 76: 101-2. [CrossRef]
• 27. Elsherbiny NM, Sharma I, Kira D, Alhusban S, Samra YA, Jadeja R et al. Homocysteine Induces Inflammation in Retina and Brain. Biomolecules 2020; 10: 393. [CrossRef]
• 28. McCully KS, Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. The American journal of pathology 1969; 56: 111-28.
• 29. Bellamy MF, McDowell IFW. Putative mechanisms for vascular damage by homocysteine. Journal of Inherited Metabolic Disease 1997; 20: 307-15. [CrossRef]
• 30. Chen S, Wu P, Zhou L, Shen Y, Li Y, Song H. Relationship between increase of serum homocysteine caused by smoking and oxidative damage in elderly patients with cardiovascular disease. International journal of clinical and experimental medicine 2015; 8: 4446-54.
• 31. Sikora M, Lewandowska I, Marczak Ł, Bretes E, Jakubowski H. Cystathionine β-synthase deficiency: different changes in proteomes of thrombosis-resistant Cbs(-/-) mice and thrombosis-prone CBS(/-) humans. Scientific reports 2020; 10: 10726. [CrossRef]
• 32. de Rezende MM, D'Almeida V. Central and systemic responses to methionine-induced hyperhomocysteinemia in mice. PloS one 2014; 9: e105704. [CrossRef]
• 33. Hånell A, Marklund N. Structured evaluation of rodent behavioral tests used in drug discovery research. Frontiers in Behavioral Neuroscience 2014; 8. [CrossRef]
• 34. Thériault R-K, Perreault ML. Hormonal regulation of circuit function: sex, systems and depression. Biology of sex differences 2019; 10: 12. [CrossRef]
• 35. Eltokhi A, Kurpiers B, Pitzer C. Behavioral tests assessing neuropsychiatric phenotypes in adolescent mice reveal strain- and sex-specific effects. Scientific Reports 2020; 10: 11263. [CrossRef]
• 36. Darcet F, Mendez-David I, Tritschler L, Gardier AM, Guilloux J-P, David DJ. Learning and memory impairments in a neuroendocrine mouse model of anxiety/depression. Frontiers in Behavioral Neuroscience 2014; 8. [CrossRef]
• 37. Beal MF. Aging, energy, and oxidative stress in neurodegenerative diseases. Ann Neurol 1995; 38: 357-66. [CrossRef]
• 38. Mattson MP. Apoptosis in neurodegenerative disorders. Nature Reviews Molecular Cell Biology 2000; 1: 120-30. [CrossRef]
• 39. Kowalski K, Mulak A. Brain-Gut-Microbiota Axis in Alzheimer's Disease. Journal of neurogastroenterology and motility 2019; 25: 4860. [CrossRef]
• 40. Bulgart HR, Neczypor EW, Wold LE, Mackos AR. Microbial involvement in Alzheimer disease development and progression. Mol Neurodegener 2020; 15: 42. [CrossRef]
• 41. Saez-Atienzar S, Masliah E. Cellular senescence and Alzheimer disease: the egg and the chicken scenario. Nat Rev Neurosci 2020; 21: 433-44. [CrossRef]
• 42. Calcinotto A, Kohli J, Zagato E, Pellegrini L, Demaria M, Alimonti A. Cellular Senescence: Aging, Cancer, and Injury. Physiol Rev 2019; 99: 1047-78. [CrossRef]
• 43. Piechota M, Sunderland P, Wysocka A, Nalberczak M, Sliwinska MA, Radwanska K, et al. Is senescence-associated β-galactosidase a marker of neuronal senescence? Oncotarget 2016; 7: 81099-109. [CrossRef]
• 44. Muñoz-Espín D, Serrano M. Cellular senescence: from physiology to pathology. Nature Reviews Molecular Cell Biology 2014; 15: 482-96. [CrossRef]
• 45. Muñoz-Espín D, Cañamero M, Maraver A, Gómez-López G, Contreras J, Murillo-Cuesta S, et al. Programmed Cell Senescence during Mammalian Embryonic Development. Cell 2013; 155: 1104-18. [CrossRef]