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Regulation of Neprilysin Activity and Cognitive Functions in Rats After Prenatal Hypoxia

  • I. A. ZhuravinEmail author
  • N. M. Dubrovskaya
  • D. S. Vasilev
  • D. I. Kozlova
  • E. G. Kochkina
  • N. L. Tumanova
  • N. N. Nalivaeva
Original Paper

Abstract

The amyloid-degrading enzyme neprilysin (NEP) is one of the therapeutic targets in prevention and treatment of Alzheimer’s disease (AD). As we have shown previously NEP expression in rat parietal cortex (Cx) and hippocampus (Hip) decreases with age and is also significantly reduced after prenatal hypoxia. Following the paradigms for enhancement of NEP expression and activity developed in cell culture, we analysed the efficacy of various compounds able to upregulate NEP using our model of prenatal hypoxia in rats. In addition to the previous data demonstrating that valproic acid can upregulate NEP expression both in neuroblastoma cells and in rat Cx and Hip we have further confirmed that caspase inhibitors can also restore NEP expression in rat Cx reduced after prenatal hypoxia. Here we also report that administration of a green tea catechin epigallocatechin-3-gallate (EGCG) to adult rats subjected to prenatal hypoxia increased NEP activity in blood plasma, Cx and Hip as well as improved memory performance in the 8-arm maze and novel object recognition tests. Moreover, EGCG administration led to an increased number of dendritic spines in the hippocampal CA1 area which correlated with memory enhancement. The data obtained allowed us to conclude that the decrease in the activity of the amyloid-degrading enzyme NEP, as well as a reduction in the number of labile interneuronal contacts in the hippocampus, contribute to early cognitive deficits caused by prenatal hypoxia and that there are therapeutic avenues to restore these deficits via NEP activation which could also be used for designing preventive strategies in AD.

Keywords

Alzheimer’s disease Neprilysin Novel object recognition test Prenatal hypoxia Epigallocatechin gallate (EGCG) Dendritic spines 

Notes

Acknowledgements

Authors express their deepest gratitude to Prof Anthony J Turner for long-lasting collaboration and scientific guidance.

Funding

Supported by Russian Foundation for Basic Research (RFFI-19-015-00232) and Russian state budget (assignment AAAA-A18-118012290373-7).

Compliance with Ethical Standards

Conflict of interest

Authors declare no conflict of interest.

Ethical Approval

All current international, national, and institutional guidelines for the care and use of experimental animals were followed.

References

  1. 1.
    Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 8:595–608CrossRefGoogle Scholar
  2. 2.
    Thal DR, Griffin WS, Braak H (2008) Parenchymal and vascular Aβ-deposition and its effects on the degeneration of neurons and cognition in Alzheimer’s disease. J Cell Mol Med 12:1848–1862CrossRefGoogle Scholar
  3. 3.
    De Strooper B (2010) Proteases and proteolysis in Alzheimer disease: a multifactorial view on the disease process. Physiol Rev 90:465–494CrossRefGoogle Scholar
  4. 4.
    Hooper NM, Trew AJ, Parkin ET, Turner AJ (2000) The role of proteolysis in Alzheimer’s disease. Adv Exp Med Biol 477:379–390CrossRefGoogle Scholar
  5. 5.
    Nalivaeva NN, Beckett C, Belyaev ND, Turner AJ (2012) Are amyloid-degrading enzymes viable therapeutic targets in Alzheimer’s disease? J Neurochem 120(Suppl 1):167–185CrossRefGoogle Scholar
  6. 6.
    Carmona S, Hardy J, Guerreiro R (2018) The genetic landscape of Alzheimer disease. Handb Clin Neurol 148:395–408CrossRefGoogle Scholar
  7. 7.
    Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, Yarasheski KE, Bateman RJ (2010) Decreased clearance of CNS β-amyloid in Alzheimer’s disease. Science 330:1774CrossRefGoogle Scholar
  8. 8.
    Barnes K, Turner AJ, Kenny AJ (1993) An immunoelectron microscopic study of pig substantia nigra shows co-localization of endopeptidase-24.11 with substance P. Neuroscience 53:1073–1082CrossRefGoogle Scholar
  9. 9.
    Barnes K, Doherty S, Turner AJ (1995) Endopeptidase-24.11 is the integral membrane peptidase initiating degradation of somatostatin in the hippocampus. J Neurochem 64:1826–1832CrossRefGoogle Scholar
  10. 10.
    Belyaev ND, Nalivaeva NN, Makova NZ, Turner AJ (2009) Neprilysin gene expression requires binding of the amyloid precursor protein intracellular domain to its promoter: implications for Alzheimer disease. EMBO Rep 10:94–100CrossRefGoogle Scholar
  11. 11.
    Marr RA, Rockenstein E, Mukherjee A, Kindy MS, Hersh LB, Gage FH, Verma IM, Masliah E (2003) Neprilysin gene transfer reduces human amyloid pathology in transgenic mice. J Neurosci 23:1992–1996CrossRefGoogle Scholar
  12. 12.
    Hama E, Shirotani K, Iwata N, Saido TC (2004) Effects of neprilysin chimeric proteins targeted to subcellular compartments on amyloid beta peptide clearance in primary neurons. J Biol Chem 279:30259–30264CrossRefGoogle Scholar
  13. 13.
    Miners JS, Van Helmond Z, Chalmers K, Wilcock G, Love S, Kehoe PG (2006) Decreased expression and activity of neprilysin in Alzheimer disease are associated with cerebral amyloid angiopathy. J Neuropathol Exp Neurol 65:1012–1021CrossRefGoogle Scholar
  14. 14.
    Wang DS, Lipton RB, Katz MJ, Davies P, Buschke H, Kuslansky G, Verghese J, Younkin SG, Eckman C, Dickson DW (2005) Decreased neprilysin immunoreactivity in Alzheimer disease, but not in pathological aging. J Neuropathol Exp Neurol 64:378–385CrossRefGoogle Scholar
  15. 15.
    Nalivaeva NN, Belyaev ND, Zhuravin IA, Turner AJ (2012) The Alzheimer’s amyloid-degrading peptidase, neprilysin: can we control it? Int J Alzheimers Dis 2012:383796Google Scholar
  16. 16.
    Fisk L, Nalivaeva NN, Boyle JP, Peers CS, Turner AJ (2007) Effects of hypoxia and oxidative stress on expression of neprilysin in human neuroblastoma cells and rat cortical neurones and astrocytes. Neurochem Res 32:1741–1748CrossRefGoogle Scholar
  17. 17.
    Nalivaeva NN, Fisk L, Kochkina EG, Plesneva SA, Zhuravin IA, Babusikova E, Dobrota D, Turner AJ (2004) Effect of hypoxia/ischemia and hypoxic preconditioning/reperfusion on expression of some amyloid-degrading enzymes. Ann N Y Acad Sci 1035:21–33CrossRefGoogle Scholar
  18. 18.
    Dubrovskaia NM, Nalivaeva NN, Plesneva SA, Feponova AA, Turner AJ, Zhuravin IA (2009) Changes in the activity of amyloid-degrading metallopeptidases leads to disruption of memory in rats. Zh Vyssh Nerv Deiat Im I P Pavlova 59:630–638Google Scholar
  19. 19.
    Mouri A, Zou LB, Iwata N, Saido TC, Wang D, Wang MW, Noda Y, Nabeshima T (2006) Inhibition of neprilysin by thiorphan (i.c.v.) causes an accumulation of amyloid β and impairment of learning and memory. Behav Brain Res 168:83–91CrossRefGoogle Scholar
  20. 20.
    Zhuravin IA, Dubrovskaya NM, Tumanova NL, Vasilev DS, Nalivaeva NN (2018) Ontogenetic and phylogenetic approaches for studying the mechanisms of cognitive dysfunctions. In: Levchenko VF (ed) Evolutionary. Physiology and Biochemistry Advances and Perspectives. Norderstedt, InTech, pp 205–224Google Scholar
  21. 21.
    Nalivaeva NN, Belyaev ND, Lewis DI, Pickles AR, Makova NZ, Bagrova DI, Dubrovskaya NM, Plesneva SA, Zhuravin IA, Turner AJ (2012) Effect of sodium valproate administration on brain neprilysin expression and memory in rats. J Mol Neurosci 46:569–577CrossRefGoogle Scholar
  22. 22.
    Kerridge C, Belyaev ND, Nalivaeva NN, Turner AJ (2014) The Aβ-clearance protein transthyretin, like neprilysin, is epigenetically regulated by the amyloid precursor protein intracellular domain. J Neurochem 130:419–431CrossRefGoogle Scholar
  23. 23.
    Kerridge C, Kozlova DI, Nalivaeva NN, Turner AJ (2015) Hypoxia affects neprilysin expression through caspase activation and an APP intracellular domain-dependent mechanism. Front Neurosci 9:426CrossRefGoogle Scholar
  24. 24.
    Pardossi-Piquard R, Petit A, Kawarai T, Sunyach C, Alves da Costa C, Vincent B, Ring S, D’Adamio L, Shen J, Müller U, St George Hyslop P, Checler F (2005) Presenilin-dependent transcriptional control of the Aβ-degrading enzyme neprilysin by intracellular domains of βAPP and APLP. Neuron 46:541–554CrossRefGoogle Scholar
  25. 25.
    Belyaev ND, Kellett KA, Beckett C, Makova NZ, Revett TJ, Nalivaeva NN, Hooper NM, Turner AJ (2010) The transcriptionally active amyloid precursor protein (APP) intracellular domain is preferentially produced from the 695 isoform of APP in a β-secretase-dependent pathway. J Biol Chem 285:41443–41454CrossRefGoogle Scholar
  26. 26.
    Venugopal C, Pappolla MA, Sambamurti K (2007) Insulysin cleaves the APP cytoplasmic fragment at multiple sites. Neurochem Res 32:2225–2234CrossRefGoogle Scholar
  27. 27.
    Vasilev DS, Dubrovskaya NM, Nalivaeva NN, Zhuravin IA (2016) Regulation of caspase-3 content and activity in rat cortex in norm and after prenatal hypoxia. Neurochem J 10:144–150CrossRefGoogle Scholar
  28. 28.
    Kozlova DI, Vasylev DS, Dubrovskaya NM, Nalivaeva NN, Tumanova NL, Zhuravin IA (2015) Role of caspase-3 in regulation of the amyloid-degrading neuropeptidase neprilysin level in the rat cortex after hypoxia. J Evol Biochem Physiol 51:480–484CrossRefGoogle Scholar
  29. 29.
    Dubrovskaya NM, Tikhonravov DL, Alekseeva OS, Zhuravin IA (2017) Recovery of learning and memory impaired by prenatal hypoxic stress in rats after injection of caspase-3 inhibitor during early ontogenesis. J Evol Biochem Physiol 53:66–68CrossRefGoogle Scholar
  30. 30.
    Melzig MF, Janka M (2003) Enhancement of neutral endopeptidase activity in SK-N-SH cells by green tea extract. Phytomedicine 10:494–498CrossRefGoogle Scholar
  31. 31.
    Ayoub S, Melzig MF (2006) Induction of neutral endopeptidase (NEP) activity of SK-N-SH cells by natural compounds from green tea. J Pharm Pharmacol 58:495–501CrossRefGoogle Scholar
  32. 32.
    Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG (2010) Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 8:e1000412CrossRefGoogle Scholar
  33. 33.
    Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 4th edn. Academic Press, San Diego, p 474Google Scholar
  34. 34.
    Dubrovskaya NM, Nalivaeva NN, Turner AJ, Zhuravin IA (2006) Effects of an inhibitor of α-secretase, which metabolizes the amyloid peptide precursor, on memory formation in rats. Neurosci Behav Physiol 36:911–913CrossRefGoogle Scholar
  35. 35.
    Ennaceur A, Delacour J (1988) A new one-trial test for neurobiological studies of memory in rats. 1: behavioral data. Behav Brain Res 31:47–59CrossRefGoogle Scholar
  36. 36.
    Dubrovskaya NM, Zhuravin IA (2010) Ontogenetic characteristics of behavior in rats subjected to hypoxia on day 14 or day 18 of embryogenesis. Neurosci Behav Physiol 40:231–238CrossRefGoogle Scholar
  37. 37.
    Turner AJ, Isaac RE, Coates D (2001) The neprilysin (NEP) family of zinc metalloendopeptidases: genomics and function. BioEssays 23:261–269CrossRefGoogle Scholar
  38. 38.
    Bland ND, Pinney JW, Thomas JE, Turner AJ, Isaac RE (2008) Bioinformatic analysis of the neprilysin (M13) family of peptidases reveals complex evolutionary and functional relationships. BMC Evol Biol 8:16CrossRefGoogle Scholar
  39. 39.
    Kerr MA, Kenny AJ (1974) The purification and specificity of a neutral endopeptidase from rabbit kidney brush border. Biochem J 137:477–488CrossRefGoogle Scholar
  40. 40.
    Nalivaeva NN (2013) Turner AJ (2013) Neprilysin. In: Rawlings Neil D, Salvesen Guy S (eds) Handbook of proteolytic enzymes. Academic Press, Oxford, pp 612–619CrossRefGoogle Scholar
  41. 41.
    Gaudoux F, Boileau G, Crine P (1993) Localization of neprilysin (EC 3.4.24.11) mRNA in rat brain by in situ hybridization. J Neurosci Res 34:426–433CrossRefGoogle Scholar
  42. 42.
    Kioussi C, Matsas R (1991) Endopeptidase-24.11, a cell-surface peptidase of central nervous system neurons, is expressed by Schwann cells in the pig peripheral nervous system. J Neurochem 57:431–440CrossRefGoogle Scholar
  43. 43.
    Turner AJ, Tanzawa K (1997) Mammalian membrane metallopeptidases: NEP, ECE, KELL, and PEX. FASEB J 11:355–364CrossRefGoogle Scholar
  44. 44.
    Carson JA, Turner AJ (2002) β-Amyloid catabolism: roles for neprilysin (NEP) and other metallopeptidases? J Neurochem 81:1–8CrossRefGoogle Scholar
  45. 45.
    Wang J, Gu BJ, Masters CL, Wang YJ (2017) A systemic view of Alzheimer disease—insights from amyloid-β metabolism beyond the brain. Nat Rev Neurol 13:612–623CrossRefGoogle Scholar
  46. 46.
    Zou LB, Mouri A, Iwata N, Saido TC, Wang D, Wang MW, Mizoguchi H, Noda Y, Nabeshima T (2006) Inhibition of neprilysin by infusion of thiorphan into the hippocampus causes an accumulation of amyloid β and impairment of learning and memory. J Pharmacol Exp Ther 317:334–340CrossRefGoogle Scholar
  47. 47.
    Caccamo A, Oddo S, Sugarman MC, Akbari Y, LaFerla FM (2005) Age- and region-dependent alterations in Aβ-degrading enzymes: implications for Aβ-induced disorders. Neurobiol Aging 26:645–654CrossRefGoogle Scholar
  48. 48.
    Nalivaeva NN, Belyaev ND, Kerridge C, Turner AJ (2014) Amyloid-clearing proteins and their epigenetic regulation as a therapeutic target in Alzheimer’s disease. Front Aging Neurosci 6:235CrossRefGoogle Scholar
  49. 49.
    Nalivaeva NN, Turner AJ (2018) Targeting amyloid clearance in Alzheimer’s disease as a therapeutic strategy. Br J Pharmacol.  https://doi.org/10.1111/bph.14593 Google Scholar
  50. 50.
    Nalivaeva NN, Turner AJ, Zhuravin IA (2018) Role of prenatal hypoxia in brain development, cognitive functions and neurodegeneration. Front Neurosci 12:825CrossRefGoogle Scholar
  51. 51.
    Zhuravin IA, Dubrovskaya NM, Vasilev DS, Tumanova NL, Nalivaeva NN (2011) Epigenetic and pharmacological regulation of the amyloid-degrading enzyme neprilysin results in modulation of cognitive functions in mammals. Dokl Biol Sci 438:145–148CrossRefGoogle Scholar
  52. 52.
    Yamamoto N, Shibata M, Ishikuro R, Tanida M, Taniguchi Y, Ikeda-Matsuo Y et al (2017) Epigallocatechin gallate induces extracellular degradation of amyloid β-protein by increasing neprilysin secretion from astrocytes through activation of ERK and PI3 K pathways. Neuroscience 362:70–78CrossRefGoogle Scholar
  53. 53.
    Chang X, Rong C, Chen Y, Yang C, Hu Q, Mo Y et al (2015) (-)-Epigallocatechin 3-gallate attenuates cognitive deterioration in Alzheimer’s disease model mice by upregulating neprilysin expression. Exp Cell Res 334:136–145CrossRefGoogle Scholar
  54. 54.
    Muenzner M, Tappenbeck N, Gembardt F, Rülke R, Furkert J, Melzig MF, Siems WE, Brockmann GA, Walther T (2016) Green tea reduces body fat via upregulation of neprilysin. Int J Obes (Lond) 40:1850–1855CrossRefGoogle Scholar
  55. 55.
    Jackson D, Connolly K, Batacan R, Ryan K, Vella R, Fenning A (2018) (−)-Epicatechin reduces blood pressure and improves left ventricular function and compliance in deoxycorticosterone acetate-salt hypertensive rats. Molecules 23(7):1511CrossRefGoogle Scholar
  56. 56.
    Rees A, Dodd G, Spencer JPE (2018) The effects of flavonoids on cardiovascular health: a review of human intervention trials and implications for cerebrovascular function. Nutrients 10(12):1852CrossRefGoogle Scholar
  57. 57.
    Rice GI, Jones AL, Grant PJ, Carter AM, Turner AJ, Hooper NM (2006) Circulating activities of angiotensin-converting enzyme, its homolog, angiotensin-converting enzyme 2, and neprilysin in a family study. Hypertension 48:914–920CrossRefGoogle Scholar
  58. 58.
    Abib RT, Peres KC, Barbosa AM, Peres TV, Bernardes A, Zimmermann LM, Quincozes-Santos A, Fiedler HD, Leal RB, Farina M, Gottfried C (2011) Epigallocatechin-3-gallate protects rat brain mitochondria against cadmium-induced damage. Food Chem Toxicol 49:2618–2623CrossRefGoogle Scholar
  59. 59.
    Fujiki H, Watanabe T, Sueoka E, Rawangkan A, Suganuma M (2018) Cancer prevention with green tea and its principal constituent, EGCG: from early investigations to urrent docus on human cancer stem cells. Mol Cells 41:73–82Google Scholar
  60. 60.
    André DM, Horimoto CM, Calixto MC, Alexandre EC, Antunes E (2018) Epigallocatechin-3-gallate protects against the exacerbation of allergic eosinophilic inflammation associated with obesity in mice. Int Immunopharmacol 62:212–219CrossRefGoogle Scholar
  61. 61.
    Singh NA, Bhardwaj V, Ravi C, Ramesh N, Mandal AKA, Khan ZA (2018) EGCG nanoparticles attenuate aluminum chloride induced neurobehavioral deficits, β amyloid and tau pathology in a rat model of Alzheimer’s Disease. Front Aging Neurosci 10:244CrossRefGoogle Scholar
  62. 62.
    Pervin M, Unno K, Ohishi T, Tanabe H, Miyoshi N, Nakamura Y (2018) Beneficial effects of green tea catechins on neurodegenerative diseases. Molecules 23:1297CrossRefGoogle Scholar
  63. 63.
    Kim E, Bisson WH, Löhr CV, Williams DE, Ho E, Dashwood RH, Rajendran P (2016) Histone and non-histone targets of dietary deacetylase inhibitors. Curr Top Med Chem 16:714–731CrossRefGoogle Scholar
  64. 64.
    Khalil H, Tazi M, Caution K, Ahmed A, Kanneganti A, Assani K, Kopp B, Marsh C, Dakhlallah D, Amer AO (2016) Aging is associated with hypermethylation of autophagy genes in macrophages. Epigenetics 11:381–388CrossRefGoogle Scholar
  65. 65.
    Rodrigues J, Assunção M, Lukoyanov N, Cardoso A, Carvalho F, Andrade JP (2013) Protective effects of a catechin-rich extract on the hippocampal formation and spatial memory in aging rats. Behav Brain Res 246:94–102CrossRefGoogle Scholar
  66. 66.
    Guo Y, Zhao Y, Nan Y, Wang X, Chen Y, Wang S (2017) (−)-Epigallocatechin-3-gallate ameliorates memory impairment and rescues the abnormal synaptic protein levels in the frontal cortex and hippocampus in a mouse model of Alzheimer’s disease. NeuroReport 28:590–597CrossRefGoogle Scholar
  67. 67.
    Souchet B, Guedj F, Penke-Verdier Z, Daubigney F, Duchon A, Herault Y, Bizot JC, Janel N, Créau N, Delatour B, Delabar JM (2015) Pharmacological correction of excitation/inhibition imbalance in Down syndrome mouse models. Front Behav Neurosci 9:267CrossRefGoogle Scholar
  68. 68.
    Lee B, Shim I, Lee H, Hahm DH (2018) Effects of epigallocatechin gallate on behavioral and cognitive impairments, hypothalamic-pituitary-adrenal axis dysfunction, and alternations in hippocampal BDNF expression under single prolonged stress. J Med Food 21:979–989CrossRefGoogle Scholar
  69. 69.
    Zhang H, Su S, Yu X, Li Y (2017) Dietary epigallocatechin 3-gallate supplement improves maternal and neonatal treatment outcome of gestational diabetes mellitus: a double-blind randomised controlled trial. J Hum Nutr Diet 30:753–758CrossRefGoogle Scholar
  70. 70.
    Cetin-Karaca H, Newman MC (2018) Antimicrobial efficacy of phytochemicals against Bacillus cereus in reconstituted infant rice cereal. Food Microbiol 69:189–195CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • I. A. Zhuravin
    • 1
    • 2
    Email author
  • N. M. Dubrovskaya
    • 1
    • 2
  • D. S. Vasilev
    • 1
    • 2
  • D. I. Kozlova
    • 1
    • 3
  • E. G. Kochkina
    • 1
  • N. L. Tumanova
    • 1
  • N. N. Nalivaeva
    • 1
    • 4
  1. 1.I.M. Sechenov Institute of Evolutionary Physiology and BiochemistryRussian Academy of SciencesSt. PetersburgRussia
  2. 2.Research CentreSaint-Petersburg State Pediatric Medical UniversitySt. PetersburgRussia
  3. 3.LLC Scientific and Production Company “ABRIS +”St. PetersburgRussia
  4. 4.School of Biomedical Sciences, Faculty of Biological SciencesUniversity of LeedsLeedsUK

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