Hostname: page-component-78c5997874-dh8gc Total loading time: 0 Render date: 2024-11-18T06:11:17.851Z Has data issue: false hasContentIssue false
  • English
  • Français

The role of MMP genes in recurrent depressive disorders and cognitive functions

Published online by Cambridge University Press:  09 February 2016

Kinga Bobińska ,
Janusz Szemraj ,
Piotr Gałecki  and
Monika Talarowska
Kinga Bobińska
Affiliation:
Department of Adult Psychiatry, Medical University of Lodz, Lodz, Poland
Janusz Szemraj
Affiliation:
Department of Medical Biochemistry, Medical University of Lodz, Lodz, Poland
Piotr Gałecki
Affiliation:
Department of Adult Psychiatry, Medical University of Lodz, Lodz, Poland
Monika Talarowska*
Affiliation:
Department of Adult Psychiatry, Medical University of Lodz, Lodz, Poland
*
Monika Talarowska, Department of Adult Psychiatry, Medical University of Lodz, Lodz, Poland, Aleksandrowska 159, 91-229 Lodz, Poland. Tel: +4 842 775 1986; Fax: +4 842 640 5058; E-mail: talarowskamonika@wp.pl
Get access Rights & Permissions [Opens in a new window]

Abstract

Objective

Among the 28 metalloproteinases described so far, 23 can be found in the human organism, but only few are expressed in the human brain. The main objective of this study was to analyse the relationship between MMP-2, MMP-9 and TIMP-2 gene expression and cognitive performance.

Methods

The study comprised 234 subjects: patients suffering from recurrent depressive disorder (rDD, n=139) and healthy subjects (HS, n=95). The cognitive function assessment was carried out with the help of the following tests: Trail Making Test, The Stroop Test, Verbal Fluency Test and Auditory Verbal Learning Test. Gene expression on the mRNA and protein level was evaluated for MMP-2, MMP-9 and TIMP-2 in both groups using RNA extraction, reverse transcription and enzyme-linked immunosorbent assay.

Results

Both mRNA and protein expression levels of all the genes were significantly lower in rDD subjects as compared with HS. Having analysed the entire experimental group (N=234), significant interrelations were found between the expression of the analysed genes and the results of the tests used to measure cognitive functions. Increased expression on both the mRNA and the protein level was associated in each case with better performance of all the tests conducted. After carrying out a separate analysis on the people from the rDD group and the HS group, similar dependencies were still observed.

Conclusions

The results of our study show decreased expression of MMP-2, MMP-9 and TIMP-2 genes on both mRNA and protein levels in depression. Elevated expression of MMP-2, MMP-9, TIMP-2 positively affects cognitive efficiency: working memory, executive functions, attention functions, direct and delayed auditory–verbal memory, the effectiveness of learning processes and verbal fluency. The study highlights the important role of peripheral matrix metalloproteinases genes in depression and cognitive functions.

Keywords

cognitiondepressionMMPs
Type
Original Articles
Information
Acta Neuropsychiatrica , Volume 28 , Issue 4 , August 2016 , pp. 221 - 231
Check for updates
Copyright
© Scandinavian College of Neuropsychopharmacology 2016 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1. Yong, VW, Krekoski, CA, Forsyth, PA, Bell, R, Edwards, DR. Matrix metalloproteinases and diseases of the CNS. Trends Neurosci 1998;21:75–80.Google Scholar
2. Romi, F, Helgeland, G, Gilhus, NE. Serum levels of matrix metalloproteinases: implications in clinical neurology. Eur Neurol 2012;67:121–128.CrossRefGoogle ScholarPubMed
3. Stomrud, E, Björkqvist, M, Janciauskiene, S, Minthon, L, Hansson, O. Alterations of matrix metalloproteinases in the healthy elderly with increased risk of prodromal Alzheimer’s disease. Alzheimers Res Ther 2010;2:20.Google Scholar
4. Kurzepa, J, Bartosik-Psujek, H, Suchozebrska-Jesionek, D, Rejdak, K, Stryjecka-Zimmer, M, Stelmasiak, Z. Role of matrix metalloproteinases in the pathogenesis of multiple sclerosis. Neurologiaineurochirurgiapolska 2005;39:63–67.Google Scholar
5. Demestre, M, Parkin-Smith, G, Petzold, A, Pullen, AH. The pro and the active form of matrix metalloproteinase-9 is increased in serum of patients with amyotrophic lateral sclerosis. J Neuroimmunol 2005;159:146–154.Google Scholar
6. Rosenberg, GA, Sullivan, N, Esiri, MM. White matter damage is associated with matrix metalloproteinases in vascular dementia. Stroke 2001;32:1162–1168.CrossRefGoogle ScholarPubMed
7. Rosenberg, GA, Prestopnik, J, Adair, JC et al. Validation of biomarkers in subcortical ischaemic vascular disease of the Binswanger type: approach to targeted treatment trials. J Neurol Neurosurg Psychiatry 2015;86:1324–1330.Google Scholar
8. Yang, Y, Hill, JW, Rosenberg, GA. Multiple roles of metalloproteinases in neurological disorders. Prog Mol Biol Transl Sci 2011;99:241–263.Google Scholar
9. Kowalski, M, Walczak, A, Majsterek, I. Matrix metalloproteinases (MMPs): modern molecular markers of open-angle glaucoma diagnosis and therapy. Post Hig Med Dosw 2008;62:584–585.Google Scholar
10. Agrawal, SM, Lau, L, Yong, VW. MMPs in the central nervous system: where the good guys go bad. Semin Cell Dev Biol 2008;19:42–51.Google Scholar
11. Kaczmarek, L, Lapinska-Dzwonek, J, Szymczak, S. Matrix metalloproteinases in the adult brain physiology: a link between c-Fos, AP-1 and remodeling of neuronal connections? EMBO J 2002;21:6643–6648.Google Scholar
12. Michaluk, P, Kaczmarek, L. Matrix metalloproteinase-9 in glutamate-dependent adult brain function and dysfunction. Cell Death Differ 2007;14:1255–1258.Google Scholar
13. Renaud, S, Erne, B, Fuhr, P et al. Matrix metalloproteinases-9 and -2 in secondary vasculitic neuropathies. Acta Neuropathol 2003;105:37–42.Google Scholar
14. Mannello, F, Medda, V. Nuclear localization of matrix metalloproteinases. Prog Histochem Cytochem 2012;47:27–58.CrossRefGoogle ScholarPubMed
15. Rascher, G, Fischmann, A, Kroger, S, Duffner, F, Grote, EH, Wolburg, H. Extracellular matrix and the blood-brain barrier in glioblastoma multiforme: spatial segregation of tenascin and agrin. Actaneuropathologica 2002;104:85–91.Google Scholar
16. Candelario-Jalil, E, Thompson, J, Taheri, S et al. Matrix metalloproteinases are associated with increased blood-brain barrier opening in vascular cognitive impairment. Stroke 2011;42:1345–1350.Google Scholar
17. Wójcik-Stanaszek, L, Sypecka, J, Szymczak, P et al. The potential role of metalloproteinases in neurogenesis in the gerbil hippocampus following global forebrain ischemia. PLoS One 2011;6:e22465.Google Scholar
18. Pawlak, R, Rao, BS, Melchor, JP, Chattarji, S, McEwen, B, Strickland, S. Tissue plasminogen activator and plasminogen mediate stress induced decline of neuronal and cognitive functions in the mouse hippocampus. Proc Natl Acad Sci USA 2005;102:18201–18206.Google Scholar
19. Fainardi, E, Castellazzi, M, Bellini, T et al. Cerebrospinal fluid and serum levels and intrathecal production of active matrix metalloproteinase-9 (MMP-9) as markers of disease activity in patients with multiple sclerosis. Mult Scler 2006;12:294–301.Google Scholar
20. World Health Organization. ICD-10 classification of mental & behavioural disorders. Geneva: World Health Organization, 1993.Google Scholar
21. Patten, S. Performance of the Composite International Diagnostic Interview Short Form for major depression in community and clinical samples. Chron Dis Can 1997;3:18–24.Google Scholar
22. Lezak, MD. Neuropsychological assessment. New York, Oxford: Oxford University Press, 2004.Google Scholar
23. Talarowska, M, Gałecki, P, Maes, M, Bobińska, K, Kowalczyk, E. Total antioxidant status correlates with cognitive impairment in patients with recurrent depressive disorder. Neurochem Res 2012;37:1761–1767.Google Scholar
24. Winer, J, Jung, CK, Shackel, I, Williams, PM. Development and validation of real-time quantitative reverse transcriptase-polymerase chain reaction for monitoring gene expression in cardiac myocytes in vitro. Anal Biochem 1999;270:41–49.CrossRefGoogle ScholarPubMed
25. Luz Sampieri, C, Pena, S, Ochoa-lara, M, Zeneto-Cuevas, R, Leon-Cordoba, K. Expression of matrix metalloproteinases 2 and 9 in human gastric cancer and superficial gastritis. World J Gastroenterol 2010;16:1500–1505.CrossRefGoogle Scholar
26. Kirkwood, B, Sterne, J. Essential medical statistics, 2nd edn. Hoboken: Wiley-Bleckwell, 2003.Google Scholar
27. Maes, M, Lambrechts, J, Bosmans, E et al. Evidence for a systemic immune activation during depression: results of leukocyte enumeration by flow cytometry in conjunction with monoclonal antibody staining. Psychol Med 1992;22:45–53.CrossRefGoogle ScholarPubMed
28. Lutgendorf, SK, Lamkin, DM, Jennings, NB et al. Biobehavioral influences on matrix metalloproteinase expression in ovarian carcinoma. Clin Cancer Res 2008;14:6839–6846.Google Scholar
29. Lutgendorf, SK, Cole, S, Costanzo, E et al. Stress-related mediators stimulate vascular endothelial growth factor secretion by two ovarian cancer cell lines. Clin Cancer Res 2003;9:4514–4521.Google Scholar
30. Gałecki, P, Talarowska, M, Anderson, G, Berk, M, Maes, M. Mechanisms underlying neurocognitive dysfunctions in recurrent major depression. Med Sci Monit 2015;21:1535–1547.Google Scholar
31. Bjerke, M, Jonsson, M, Nordlund, A et al. Cerebrovascular biomarker profile is related to white matter disease and ventricular dilation in a LADIS substudy. Dement Geriatr Cogn Dis Extra 2014;4:385–394.Google Scholar
32. Mizoguchi, H, Takuma, K, Fukuzaki, E et al. Matrix metalloprotease-9 inhibition improves amyloid beta-mediated cognitive impairment and neurotoxicity in mice. J Pharmacol Exp Ther 2009;331:14–22.Google Scholar
33. Barichello, T, Generoso, JS, Michelon, CM et al. Inhibition of matrix metalloproteinases-2 and -9 prevents cognitive impairment induced by pneumococcal meningitis in Wistar rats. Exp Biol Med (Maywood) 2014;239:225–231.CrossRefGoogle ScholarPubMed
34. Li, S, Wu, Y, Keating, SM et al. Matrix metalloproteinase levels in early HIV infection and relation to in vivo brain status. J Neurovirol 2013;19:452–460.CrossRefGoogle ScholarPubMed
35. Jaworski, DM, Boone, J, Caterina, J et al. Prepulse inhibition and fear-potentiated startle are altered in tissue inhibitor of metalloproteinase-2 (TIMP-2) knockout mice. Brain Res 2005;1051:81–89.Google Scholar
36. Wright, JW, Brown, TE, Harding, JW. Inhibition of hippocampal matrix metalloproteinase-3 and -9 disrupts spatial memory. Neural Plast 2007;2007:73813.Google Scholar
37. Nagy, V, Bozdagi, O, Matynia, A et al. Matrix metalloproteinase-9 is required for hippocampal late-phase long-term potentiation and memory. J Neurosci 2006;26:1923–1934.Google Scholar
38. Wiera, G, Wozniak, G, Bajor, M, Kaczmarek, L, Mozrzymas, JW. Maintenance of long-term potentiation in hippocampal mossy fiber-CA3 pathway requires fine-tuned MMP-9 proteolytic activity. Hippocampus 2013;23:529–543.Google Scholar
39. Martín-Aragón, S, Bermejo-Bescós, P, Benedí, J et al. Metalloproteinase’s activity and oxidative stress in mild cognitive impairment and Alzheimer’s disease. Neurochem Res 2009;34:373–378.Google Scholar
40. Anacker, C, Scholz, J, O’Donnell, KJ et al. Neuroanatomic differences associated with stress susceptibility and resilience. Biol Psychiatry 2015; doi: 10.1016/j.biopsych.2015.08.009 [Epub ahead of print].Google Scholar
41. Donohue, HS, Gabbott, PL, Davies, HA et al. Chronic restraint stress induces changes in synapsę morphology in stratum lacunosum-moleculare CA1 rat hippocampus: a stereological and three-dimensional ultrastructural study. Neuroscience 2006;140:597–606.CrossRefGoogle ScholarPubMed
42. van der Kooij, MA, Fantin, M, Rejmak, E et al. Role for MMP-9 in stress-induced downregulation of nectin-3 in hippocampal CA1 and associated behavioural alterations. Nat Commun 2014;5:4995.Google Scholar
43. Bienkowski, P, Samochowiec, J, Pelka-Wysiecka, J et al. Functional polymorphism of matrix metalloproteinase-9 (MMP9) gene is not associated with schizophrenia and with its deficit subtype. Pharmacol Rep 2015;67:442–445.Google Scholar
44. Chopra, K, Baveja, A, Kuhad, A. MMPs: a novel drug target for schizophrenia. Expert Opin Ther Targets 2015;19:77–85.Google Scholar
45. Wright, JW, Harding, JW. Contributions of matrix metalloproteinases to neural plasticity, habituation, associative learning and drug addiction. Neural Plast 2009;2009:579382.Google Scholar
46. Ethell, IM, Ethell, DW. Matrix metalloproteinases in brain development and remodeling: synaptic functions and targets. J Neurosci Res 2007;85:2813–2823.Google Scholar
47. Leonardo, CC, Pennypacker, KR. Neuroinflammation and MMPs: potential therapeutic targets in neonatal hypoxic-ischemic injury. J Neuroinflammation 2009;6:13.Google Scholar