Table of Contents Author Guidelines Submit a Manuscript
International Journal of Alzheimer’s Disease
Volume 2012, Article ID 383796, 12 pages
http://dx.doi.org/10.1155/2012/383796
Review Article

The Alzheimer's Amyloid-Degrading Peptidase, Neprilysin: Can We Control It?

1School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK
2I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, RAS, 44 Thorez Avenue, Saint Petersburg 194223, Russia

Received 15 February 2012; Accepted 1 June 2012

Academic Editor: Fabrizio Tagliavini

Copyright © 2012 N. N. Nalivaeva et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. J. A. Hardy and G. A. Higgins, “Alzheimer's disease: the amyloid cascade hypothesis,” Science, vol. 256, no. 5054, pp. 184–185, 1992. View at Google Scholar · View at Scopus
  2. D. J. Selkoe, “The molecular pathology of Alzheimer's disease,” Neuron, vol. 6, no. 4, pp. 487–498, 1991. View at Publisher · View at Google Scholar · View at Scopus
  3. J. Hardy, “The amyloid hypothesis for Alzheimer's disease: a critical reappraisal,” Journal of Neurochemistry, vol. 110, no. 4, pp. 1129–1134, 2009. View at Publisher · View at Google Scholar · View at Scopus
  4. R. J. Castellani and M. A. Smith, “Compounding artefacts with uncertainty, and an amyloid cascade hypothesis that is ‘too big to fail’,” Journal of Pathology, vol. 224, no. 2, pp. 147–152, 2011. View at Publisher · View at Google Scholar · View at Scopus
  5. A. Goate and J. Hardy, “Twenty years of Alzheimer's disease-causing mutations,” Journal of Neurochemistry, vol. 120, supplement 1, pp. 3–8, 2012. View at Publisher · View at Google Scholar
  6. E. Karran, M. Mercken, and B. de Strooper, “The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics,” Nature Reviews Drug Discovery, vol. 10, no. 9, pp. 698–712, 2011. View at Publisher · View at Google Scholar
  7. S. Li, M. Jin, T. Koeglsperger, N. E. Shepardson, G. M. Shankar, and D. J. Selkoe, “Soluble a β oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors,” Journal of Neuroscience, vol. 31, no. 18, pp. 6627–6638, 2011. View at Publisher · View at Google Scholar · View at Scopus
  8. M. E. Larson and and S. E. Lesné, “Soluble Aβ oligomer production and toxicity,” Journal of Neurochemistry, vol. 120, supplement 1, pp. 125–139, 2012. View at Google Scholar
  9. P. S. Aisen, “The development of anti-amyloid therapy for Alzheimer's disease: from secretase modulators to polymerisation inhibitors,” CNS Drugs, vol. 19, no. 12, pp. 989–996, 2005. View at Publisher · View at Google Scholar · View at Scopus
  10. J. S. Miners, N. Barua, P. G. Kehoe et al., “Aβ-degrading enzymes: potential for treatment of Alzheimer disease,” Journal of Neuropathology and Experimental Neurology, vol. 70, no. 11, pp. 944–959, 2011. View at Google Scholar
  11. N. N. Nalivaeva, L. R. Fisk, N. D. Belyaev, and A. J. Turner, “Amyloid-degrading enzymes as therapeutic targets in Alzheimer's disease,” Current Alzheimer Research, vol. 5, no. 2, pp. 212–224, 2008. View at Publisher · View at Google Scholar · View at Scopus
  12. N. N. Nalivaeva, C. Beckett, N. D. Belyaev, and A. J. Turner, “Are amyloid-degrading enzymes viable therapeutic targets in Alzheimer's disease?” Journal of Neurochemistry, vol. 120, supplement 1, pp. 167–185, 2012. View at Google Scholar
  13. H. A. Pearson and C. Peers, “Physiological roles for amyloid β peptides,” Journal of Physiology, vol. 575, no. 1, pp. 5–10, 2006. View at Publisher · View at Google Scholar · View at Scopus
  14. J. Hardy, “Does Aβ 42 have a function related to blood homeostasis?” Neurochemical Research, vol. 32, no. 4-5, pp. 833–835, 2007. View at Publisher · View at Google Scholar · View at Scopus
  15. Y. Ohyagi, H. Asahara, D. H. Chui et al., “Intracellular Aβ42 activates p53 promoter: a pathway to neurodegeneration in Alzheimer's disease,” The FASEB Journal, vol. 19, no. 2, pp. 255–257, 2005. View at Publisher · View at Google Scholar · View at Scopus
  16. J. A. Bailey, B. Maloney, Y. W. Ge, and D. K. Lahiri, “Functional activity of the novel Alzheimer's amyloid β-peptide interacting domain (AβID) in the APP and BACE1 promoter sequences and implications in activating apoptotic genes and in amyloidogenesis,” Gene, vol. 488, no. 1-2, pp. 13–22, 2011. View at Publisher · View at Google Scholar
  17. C. A. Hawkes, W. Härtig, J. Kacza et al., “Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy,” Acta Neuropathologica, vol. 121, no. 4, pp. 431–443, 2011. View at Publisher · View at Google Scholar · View at Scopus
  18. M. A. Kerr and A. J. Kenny, “The purification and specificity of a neutral endopeptidase from rabbit kidney brush border,” Biochemical Journal, vol. 137, no. 3, pp. 477–488, 1974. View at Google Scholar · View at Scopus
  19. B. Malfroy, J. P. Swerts, A. Guyon et al., “High affinity enkephalin degrading peptidase in brain is increased after morphine,” Nature, vol. 276, no. 5687, pp. 523–526, 1978. View at Google Scholar · View at Scopus
  20. R. Matsas, I. S. Fulcher, A. J. Kenny, and A. J. Turner, “Substance P and [Leu]enkephalin are hydrolyzed by an enzyme in pig caudate synaptic membranes that is identical with the endopeptidase of kidney microvilli,” Proceedings of the National Academy of Sciences of the United States of America, vol. 80, no. 10 I, pp. 3111–3115, 1983. View at Google Scholar · View at Scopus
  21. M. Letarte, S. Vera, R. Tran et al., “Common acute lymphocytic leukemia antigen is identical to neutral endopeptidase,” Journal of Experimental Medicine, vol. 168, no. 4, pp. 1247–1253, 1988. View at Google Scholar · View at Scopus
  22. N. Morisaki, S. Moriwaki, Y. Sugiyama-Nakagiri, K. Haketa, Y. Takema, and G. Imokawa, “Neprilysin is identical to skin fibroblast elastase: its role in skin aging and UV responses,” The Journal of Biological Chemistry, vol. 285, no. 51, pp. 39819–39827, 2010. View at Publisher · View at Google Scholar · View at Scopus
  23. R. Matsas, A. J. Kenny, and A. J. Turner, “The metabolism of neuropeptides. The hydrolysis of peptides, including enkephalins, tachykinins and their analogues, by endopeptidase-24.11,” Biochemical Journal, vol. 223, no. 2, pp. 433–440, 1984. View at Google Scholar · View at Scopus
  24. J. M. Relton, N. S. Gee, R. Matsas, A. J. Turner, and A. J. Kenny, “Purification of endopeptidase-24.11 (“enkephalinase”) from pig brain by immunoadsorbent chromatography,” Biochemical Journal, vol. 215, no. 3, pp. 519–523, 1983. View at Google Scholar · View at Scopus
  25. B. Malfroy, W. J. Kuang, P. H. Seeburg, A. J. Mason, and P. R. Schofield, “Molecular cloning and amino acid sequence of human enkephalinase (neutral endopeptidase),” The FEBS Letters, vol. 229, no. 1, pp. 206–210, 1988. View at Google Scholar · View at Scopus
  26. K. Nishimura, M. Ueki, H. Kaneto, and T. Hazato, “Study of a new endogenous inhibitor of enkephalin-degrading enzymes; pharmacological function and metabolism of spinorphin,” Japanese Journal of Anesthesiology, vol. 42, no. 11, pp. 1663–1670, 1993. View at Google Scholar · View at Scopus
  27. C. Rougeot, M. Messaoudi, V. Hermitte et al., “Sialorphin, a natural inhibitor of rat membrane-bound neutral endopeptidase that displays analgesic activity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 14, pp. 8549–8554, 2003. View at Publisher · View at Google Scholar · View at Scopus
  28. A. Wisner, E. Dufour, M. Messaoudi et al., “Human Opiorphin, a natural antinociceptive modulator of opioid-dependent pathways,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 47, pp. 17979–17984, 2006. View at Publisher · View at Google Scholar · View at Scopus
  29. C. Oefner, A. D'Arcy, M. Hennig, F. K. Winkler, and G. E. Dale, “Structure of human neutral endopeptidase (neprilysin) complexed with phosphoramidon,” Journal of Molecular Biology, vol. 296, no. 2, pp. 341–349, 2000. View at Publisher · View at Google Scholar · View at Scopus
  30. A. J. Turner, R. E. Isaac, and D. Coates, “The neprilysin (NEP) family of zinc metalloendopeptidases: genomics and function,” Bioassay, vol. 23, no. 3, pp. 261–269, 2001. View at Publisher · View at Google Scholar
  31. N. D. Bland, J. W. Pinney, J. E. Thomas, A. J. Turner, and R. E. Isaac, “Bioinformatic analysis of the neprilysin (M13) family of peptidases reveals complex evolutionary and functional relationships,” BMC Evolutionary Biology, vol. 8, no. 1, article 16, 2008. View at Publisher · View at Google Scholar · View at Scopus
  32. K. Barnes, A. J. Turner, and A. J. Kenny, “An immunoelectron microscopic study of pig substantia nigra shows co-localization of endopeptidase-24.11 with substance P,” Neuroscience, vol. 53, no. 4, pp. 1073–1082, 1993. View at Publisher · View at Google Scholar · View at Scopus
  33. L. Fisk, N. N. Nalivaeva, J. P. Boyle, C. S. Peers, and A. J. Turner, “Effects of hypoxia and oxidative stress on expression of neprilysin in human neuroblastoma cells and rat cortical neurones and astrocytes,” Neurochemical Research, vol. 32, no. 10, pp. 1741–1748, 2007. View at Publisher · View at Google Scholar · View at Scopus
  34. S. E. Hickman, E. K. Allison, and J. El Khoury, “Microglial dysfunction and defective β-amyloid clearance pathways in aging alzheimer's disease mice,” Journal of Neuroscience, vol. 28, no. 33, pp. 8354–8360, 2008. View at Publisher · View at Google Scholar · View at Scopus
  35. T. W. LeBien and R. T. McCormack, “The common acute lymphoblastic leukemia antigen (CD10). Emancipation from a functional enigma,” Blood, vol. 73, no. 3, pp. 625–635, 1989. View at Google Scholar · View at Scopus
  36. C. N. Papandreou, B. Usmani, Y. P. Geng et al., “Neutral endopeptidase 24.11 loss in metastatic human prostate cancer contributes to androgen-independent progression,” Nature Medicine, vol. 4, no. 1, pp. 50–57, 1998. View at Publisher · View at Google Scholar · View at Scopus
  37. B. Göhring, H. J. Holzhausen, A. Meye et al., “Endopeptidase 24.11/CD10 is down-regulated in renal cell cancer,” International Journal of Molecular Medicine, vol. 2, no. 4, pp. 409–414, 1998. View at Google Scholar · View at Scopus
  38. A. J. Cohen, P. A. Bunn, W. Franklin et al., “Neutral endopeptidase: variable expression in human lung, inactivation in lung cancer, and modulation of peptide-induced calcium flux,” Cancer Research, vol. 56, no. 4, pp. 831–839, 1996. View at Google Scholar · View at Scopus
  39. L. D'Adamio, M. A. Shipp, E. L. Masteller, and E. L. Reinherz, “Organization of the gene encoding common acute lymphoblastic leukemia antigen (neutral endopeptidase 24.11): multiple miniexons and separate 5′ untranslated regions,” Proceedings of the National Academy of Sciences of the United States of America, vol. 86, no. 18, pp. 7103–7107, 1989. View at Google Scholar · View at Scopus
  40. C. Li, R. M. Booze, and L. B. Hersh, “Tissue-specific expression of rat neutral endopeptidase (neprilysin) mRNAs,” The Journal of Biological Chemistry, vol. 270, no. 11, pp. 5723–5728, 1995. View at Publisher · View at Google Scholar · View at Scopus
  41. B. Lu, N. P. Gerard, L. F. Kolakowski et al., “Neutral endopeptidase modulation of septic shock,” Journal of Experimental Medicine, vol. 181, no. 6, pp. 2271–2275, 1995. View at Publisher · View at Google Scholar · View at Scopus
  42. H. S. Fischer, G. Zernig, R. Schuligoi et al., “Alterations within the endogenous opioid system in mice with targeted deletion of the neutral endopeptidase (“enkephalinase”) gene,” Regulatory Peptides, vol. 96, no. 1-2, pp. 53–58, 2000. View at Publisher · View at Google Scholar · View at Scopus
  43. W. E. Siems, B. Maul, W. Krause et al., “Neutral endopeptidase and alcohol consumption, experiments in neutral endopeptidase-deficient mice,” European Journal of Pharmacology, vol. 397, no. 2-3, pp. 327–334, 2000. View at Publisher · View at Google Scholar · View at Scopus
  44. K. Barnes, R. Matsas, N. M. Hooper, A. J. Turner, and A. J. Kenny, “Endopeptidase-24.11 is striosomally ordered in pig brain and, in contrast to aminopeptidase N and peptidyl dipeptidase A (“angiotensin converting enzyme”), is a marker for a set of striatal efferent fibres,” Neuroscience, vol. 27, no. 3, pp. 799–817, 1988. View at Google Scholar · View at Scopus
  45. K. Barnes, S. Doherty, and A. J. Turner, “Endopeptidase-24.11 is the integral membrane peptidase initiating degradation of somatostatin in the hippocampus,” Journal of Neurochemistry, vol. 64, no. 4, pp. 1826–1832, 1995. View at Google Scholar · View at Scopus
  46. K. Barnes, A. J. Turner, and A. J. Kenny, “Membrane localization of endopeptidase-24.11 and peptidyl dipeptidase A (angiotensin converting enzyme) in the pig brain: a study using subcellular fractionation and electron microscopic immunocytochemistry,” Journal of Neurochemistry, vol. 58, no. 6, pp. 2088–2096, 1992. View at Publisher · View at Google Scholar · View at Scopus
  47. C. Kioussi and R. Matsas, “Endopeptidase-24.11, a cell-surface peptidase of central nervous system neurons, is expressed by Schwann cells in the pig peripheral nervous system,” Journal of Neurochemistry, vol. 57, no. 2, pp. 431–440, 1991. View at Google Scholar · View at Scopus
  48. C. Kioussi, A. Mamalaki, K. Jessen, R. Mirsky, L. B. Hersh, and R. Matsas, “Expression of endopeptidase-24.11 (common acute lymphoblastic leukaemia antigen CD10) in the sciatic nerve of the adult rat after lesion and during regeneration,” European Journal of Neuroscience, vol. 7, no. 5, pp. 951–961, 1995. View at Publisher · View at Google Scholar · View at Scopus
  49. Z. Wang, D. Yang, X. Zhang et al., “Hypoxia-induced down-regulation of neprilysin by histone modification in mouse primary cortical and Hippocampal neurons,” PLoS ONE, vol. 6, no. 4, Article ID e19229, 2011. View at Publisher · View at Google Scholar · View at Scopus
  50. Y. G. Sun and Z. F. Chen, “A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord,” Nature, vol. 448, no. 7154, pp. 700–703, 2007. View at Publisher · View at Google Scholar · View at Scopus
  51. D. I. Diz, M. A. Garcia-Espinosa, P. E. Gallagher, D. Ganten, C. M. Ferrario, and D. B. Averill, “Angiotensin-(1–7) and baroreflex function in nucleus tractus solitarii of (mRen2)27 transgenic rats,” Journal of Cardiovascular Pharmacology, vol. 51, no. 6, pp. 542–548, 2008. View at Publisher · View at Google Scholar · View at Scopus
  52. A. P. Silva, C. Cavadas, and E. Grouzmann, “Neuropeptide Y and its receptors as potential therapeutic drug targets,” Clinica Chimica Acta, vol. 326, no. 1-2, pp. 3–25, 2002. View at Publisher · View at Google Scholar · View at Scopus
  53. J. Hernández, A. B. Segarra, M. Ramírez et al., “Stress influences brain enkephalinase, oxytocinase and angiotensinase activities: a new hypothesis,” Neuropsychobiology, vol. 59, no. 3, pp. 184–189, 2009. View at Publisher · View at Google Scholar · View at Scopus
  54. C. Gandou, A. Ohtani, K. Senzaki, and T. Shiga, “Neurotensin promotes the dendrite elongation and the dendritic spine maturation of the cerebral cortex in vitro,” Neuroscience Research, vol. 66, no. 3, pp. 246–255, 2010. View at Publisher · View at Google Scholar · View at Scopus
  55. C. Sakurada, S. Sakurada, T. Orito, K. Tan-No, and T. Sakurada, “Degradation of nociceptin (orphanin FQ) by mouse spinal cord synaptic membranes is triggered by endopeptidase-24.11: an in vitro and in vivo study,” Biochemical Pharmacology, vol. 64, no. 8, pp. 1293–1303, 2002. View at Publisher · View at Google Scholar · View at Scopus
  56. N. M. Dubrovskaya, N. N. Nalivaeva, S. A. Plesneva, A. A. Feponova, A. J. Turner, and I. A. Zhuravin, “Changes in the activity of amyloid-degrading metallopeptidases leads to disruption of memory in rats,” Neuroscience and Behavioral Physiology, vol. 40, no. 9, pp. 975–980, 2010. View at Publisher · View at Google Scholar · View at Scopus
  57. N. M. Dubrovskaya, N. N. Nalivaeva, D. S. Vasilev et al., “Mechanisms of short-term working memory deficit,” in Short-Term Memory: New Research, Nova Science, New York, NY, USA, 2012. View at Google Scholar
  58. N. N. Nalivaeva, N. D. Belyaev, D. I. Lewis et al., “Effect of sodium valproate administration on brain neprilysin expression and memory in rats,” Journal of Molecular Neuroscience, vol. 46, no. 3, pp. 569–577, 2012. View at Publisher · View at Google Scholar · View at Scopus
  59. N. N. Nalivaeva, N. M. Dubrovskaya, D. S. Vasiliev et al., “Changes in the activity of amyloid-degrading enzymes affect cognitive functions in rats via alteration of the synaptopodin-positive dendritic network,” in New Frontiers in Molecular Mechanisms in Neurological and Psychiatric Disorders, E. Babusikova, D. Dobrota, J. Lehotsky, Martin, and Slovakia, Eds., vol. 1, pp. 277–285, 2011. View at Google Scholar
  60. I. A. Zhuravin, N. M. Dubrovskaya, D. S. Vasilev, N. L. Tumanova, and N. N. Nalivaeva, “Epigenetic and pharmacological regulation of the amyloid-degrading enzyme neprilysin results in modulation of cognitive functions in mammals,” Doklady Biological Sciences, vol. 438, no. 1, pp. 145–148, 2011. View at Publisher · View at Google Scholar · View at Scopus
  61. E. Abramov, I. Dolev, H. Fogel, G. D. Ciccotosto, E. Ruff, and I. Slutsky, “Amyloid-β as a positive endogenous regulator of release probability at hippocampal synapses,” Nature Neuroscience, vol. 12, no. 12, pp. 1567–1576, 2009. View at Publisher · View at Google Scholar · View at Scopus
  62. Y. Harigai, M. Natsume, F. Li, A. Ohtani, K. Senzaki, and T. Shiga, “Differential roles of calcitonin family peptides in the dendrite formation and spinogenesis of the cerebral cortex in vitro,” Neuropeptides, vol. 45, no. 4, pp. 263–272, 2011. View at Publisher · View at Google Scholar · View at Scopus
  63. A. P. Fernández, J. Serrano, L. Tessarollo, F. Cuttitta, and A. Martínez, “Lack of adrenomedullin in the mouse brain results in behavioral changes, anxiety, and lower survival under stress conditions,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 34, pp. 12581–12586, 2008. View at Publisher · View at Google Scholar · View at Scopus
  64. T. Ma and E. Klann, “Amyloid β: linking synaptic plasticity failure to memory disruption in Alzheimer's disease,” Journal of Neurochemistry, vol. 120, supplement 1, pp. 140–148, 2011. View at Publisher · View at Google Scholar
  65. H. S. Fischer, G. Zernig, K. F. Hauser, C. Gerard, L. B. Hersh, and A. Saria, “Neutral endopeptidase knockout induces hyperalgesia in a model of visceral pain, an effect related to bradykinin and nitric oxide,” Journal of Molecular Neuroscience, vol. 18, no. 1-2, pp. 129–134, 2002. View at Publisher · View at Google Scholar · View at Scopus
  66. Y. B. Wang, C. Peng, and Y. H. Liu, “Low dose of bradykinin selectively increases intracellular calcium in glioma cells,” Journal of the Neurological Sciences, vol. 258, no. 1-2, pp. 44–51, 2007. View at Publisher · View at Google Scholar · View at Scopus
  67. S. Arora and Anubhuti, “Role of neuropeptides in appetite regulation and obesity—a review,” Neuropeptides, vol. 40, no. 6, pp. 375–401, 2006. View at Publisher · View at Google Scholar · View at Scopus
  68. T. Ogawa, S. Kiryu-Seo, M. Tanaka et al., “Altered expression of neprilysin family members in the pituitary gland of sleep-disturbed rats, an animal model of severe fatigue,” Journal of Neurochemistry, vol. 95, no. 4, pp. 1156–1166, 2005. View at Publisher · View at Google Scholar · View at Scopus
  69. C. Schwarzer, “30 years of dynorphins—new insights on their functions in neuropsychiatric diseases,” Pharmacology and Therapeutics, vol. 123, no. 3, pp. 353–370, 2009. View at Publisher · View at Google Scholar · View at Scopus
  70. B. Song and J. C. G. Marvizón, “Peptidases prevent μ-opioid receptor internalization in dorsal horn neurons by endogenously released opioids,” Journal of Neuroscience, vol. 23, no. 5, pp. 1847–1858, 2003. View at Google Scholar · View at Scopus
  71. B. P. Roques, F. Noble, V. Daugé, M. C. Fournie-Zaluski, and A. Beaumont, “Neutral endopeptidase 24.11: structure, inhibition, and experimental and clinical pharmacology,” Pharmacological Reviews, vol. 45, no. 1, pp. 87–146, 1993. View at Google Scholar · View at Scopus
  72. H. H. Wang, H. L. Hsieh, and C. M. Yang, “Nitric oxide production by endothelin-1 enhances astrocytic migration via the tyrosine nitration of matrix metalloproteinase-9,” Journal of Cellular Physiology, vol. 226, no. 9, pp. 2244–2256, 2011. View at Publisher · View at Google Scholar · View at Scopus
  73. K. L. Gamble, T. Kudo, C. S. Colwell, and D. G. McMahon, “Gastrin-releasing peptide modulates fast delayed rectifier potassium current in Per1-expressing SCN neurons,” Journal of Biological Rhythms, vol. 26, no. 2, pp. 99–106, 2011. View at Publisher · View at Google Scholar · View at Scopus
  74. C. Viollet, G. Lepousez, C. Loudes, C. Videau, A. Simon, and J. Epelbaum, “Somatostatinergic systems in brain: networks and functions,” Molecular and Cellular Endocrinology, vol. 286, no. 1-2, pp. 75–87, 2008. View at Publisher · View at Google Scholar · View at Scopus
  75. H. H. Krämer, L. He, B. Lu, F. Birklein, and C. Sommer, “Increased pain and neurogenic inflammation in mice deficient of neutral endopeptidase,” Neurobiology of Disease, vol. 35, no. 2, pp. 177–183, 2009. View at Publisher · View at Google Scholar · View at Scopus
  76. T. M. Loonam, P. A. H. Noailles, J. Yu, J. P. Q. Zhu, and J. A. Angulo, “Substance P and cholecystokinin regulate neurochemical responses to cocaine and methamphetamine in the striatum,” Life Sciences, vol. 73, no. 6, pp. 727–739, 2003. View at Publisher · View at Google Scholar · View at Scopus
  77. J. P. Huston, R. U. Hasenöhrl, F. Boix, P. Gerhardt, and R. K. W. Schwarting, “Sequence-specific effects of neurokinin substance P on memory, reinforcement, and brain dopamine activity,” Psychopharmacology, vol. 112, no. 2-3, pp. 147–162, 1993. View at Google Scholar · View at Scopus
  78. R. U. Hasenöhrl, M. A. D. Souza-Silva, S. Nikolaus et al., “Substance P and its role in neural mechanisms governing learning, anxiety and functional recovery,” Neuropeptides, vol. 34, no. 5, pp. 272–280, 2000. View at Publisher · View at Google Scholar · View at Scopus
  79. S. McLean, “Do substance P and the NK1 receptor have a role in depression and anxiety?” Current Pharmaceutical Design, vol. 11, no. 12, pp. 1529–1547, 2005. View at Publisher · View at Google Scholar · View at Scopus
  80. J. Yamaoka and S. Kawana, “Rapid changes in substance P signaling and neutral endopeptidase induced by skin-scratching stimulation in mice,” Journal of Dermatological Science, vol. 48, no. 2, pp. 123–132, 2007. View at Publisher · View at Google Scholar · View at Scopus
  81. A. T. L. Hughes, C. Guilding, and H. D. Piggins, “Neuropeptide signaling differentially affects phase maintenance and rhythm generation in SCN and extra-SCN circadian oscillators,” PLoS ONE, vol. 6, no. 4, Article ID e18926, 2011. View at Publisher · View at Google Scholar · View at Scopus
  82. S. Howell, J. Nalbantoglu, and P. Crine, “Neutral endopeptidase can hydrolyze β-amyloid(1–40) but shows no effect on β-amyloid precursor protein metabolism,” Peptides, vol. 16, no. 4, pp. 647–652, 1995. View at Publisher · View at Google Scholar · View at Scopus
  83. N. Iwata, S. Tsubuki, Y. Takaki et al., “Identification of the major Aβ1–42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition,” Nature Medicine, vol. 6, no. 2, pp. 143–150, 2000. View at Publisher · View at Google Scholar · View at Scopus
  84. Y. Takaki, N. Iwata, S. Tsubuki et al., “Biochemical identification of the neutral endopeptidase family member responsible for the catabolism of amyloid β peptide in the brain,” Journal of Biochemistry, vol. 128, no. 6, pp. 897–902, 2000. View at Google Scholar · View at Scopus
  85. N. Iwata, S. Tsubuki, Y. Takaki et al., “Metabolic regulation of brain Aβ by neprilysin,” Science, vol. 292, no. 5521, pp. 1550–1552, 2001. View at Publisher · View at Google Scholar · View at Scopus
  86. E. Hama, K. Shirotani, H. Masumoto, Y. Sekine-Aizawa, H. Aizawa, and T. C. Saido, “Clearance of extracellular and cell-associated amyloid β peptide through viral expression of neprilysin in primary neurons,” Journal of Biochemistry, vol. 130, no. 6, pp. 721–726, 2001. View at Google Scholar · View at Scopus
  87. R. A. Marr, E. Rockenstein, A. Mukherjee et al., “Neprilysin gene transfer reduces human amyloid pathology in transgenic mice,” Journal of Neuroscience, vol. 23, no. 6, pp. 1992–1996, 2003. View at Google Scholar · View at Scopus
  88. B. Spencer, R. A. Marr, E. Rockenstein et al., “Long-term neprilysin gene transfer is associated with reduced levels of intracellular Aβ and behavioral improvement in APP transgenic mice,” BMC Neuroscience, vol. 9, article 109, 2008. View at Publisher · View at Google Scholar · View at Scopus
  89. K. Shirotani, S. Tsubuki, N. Iwata et al., “Neprilysin degrades both amyloid β peptides 1–40 and 1–42 most rapidly and efficiently among thiorphan- and phosphoramidon-sensitive endopeptidases,” The Journal of Biological Chemistry, vol. 276, no. 24, pp. 21895–21901, 2001. View at Publisher · View at Google Scholar · View at Scopus
  90. H. Kanemitsu, T. Tomiyama, and H. Mori, “Human neprilysin is capable of degrading amyloid β peptide not only in the monomeric form but also the pathological oligomeric form,” Neuroscience Letters, vol. 350, no. 2, pp. 113–116, 2003. View at Publisher · View at Google Scholar · View at Scopus
  91. S. Jawhar, O. Wirths, and T. A. Bayer, “Pyroglutamate amyloid-β (Aβ): a hatchet man in Alzheimer disease,” The Journal of Biological Chemistry, vol. 286, no. 45, pp. 38825–38832, 2011. View at Google Scholar
  92. S. C. Drew, C. L. Masters, and K. J. Barnham, “Alzheimer's Aβ peptides with disease-associated NTerminal modifications: Influence of isomerisation, truncation and mutation on Cu2+ coordination,” PLoS ONE, vol. 5, no. 12, Article ID e15875, 2010. View at Publisher · View at Google Scholar · View at Scopus
  93. N. N. Nalivaeva, L. Fisk, E. G. Kochkina et al., “Effect of hypoxia/ischemia and hypoxic preconditioning/reperfusion on expression of some amyloid-degrading enzymes,” Annals of the New York Academy of Sciences, vol. 1035, pp. 21–33, 2004. View at Publisher · View at Google Scholar · View at Scopus
  94. A. Caccamo, S. Oddo, M. C. Sugarman, Y. Akbari, and F. M. LaFerla, “Age- and region-dependent alterations in Aβ-degrading enzymes: implications for Aβ-induced disorders,” Neurobiology of Aging, vol. 26, no. 5, pp. 645–654, 2005. View at Publisher · View at Google Scholar · View at Scopus
  95. D. S. Wang, R. B. Lipton, M. J. Katz et al., “Decreased neprilysin immunoreactivity in Alzheimer disease, but not in pathological aging,” Journal of Neuropathology and Experimental Neurology, vol. 64, no. 5, pp. 378–385, 2005. View at Google Scholar · View at Scopus
  96. M. Carpentier, Y. Robitaille, L. DesGroseillers, G. Boileau, and M. Marcinkiewicz, “Declining expression of neprilysin in Alzheimer disease vasculature: possible involvement in cerebral amyloid angiopathy,” Journal of Neuropathology and Experimental Neurology, vol. 61, no. 10, pp. 849–856, 2002. View at Google Scholar · View at Scopus
  97. J. Apelt, K. Ach, and R. Schliebs, “Aging-related down-regulation of neprilysin, a putative β-amyloid-degrading enzyme, in transgenic Tg2576 Alzheimer-like mouse brain is accompanied by an astroglial upregulation in the vicinity of β-amyloid plaques,” Neuroscience Letters, vol. 339, no. 3, pp. 183–186, 2003. View at Publisher · View at Google Scholar · View at Scopus
  98. D. S. Wang, N. Iwata, E. Hama, T. C. Saido, and D. W. Dickson, “Oxidized neprilysin in aging and Alzheimer's disease brains,” Biochemical and Biophysical Research Communications, vol. 310, no. 1, pp. 236–241, 2003. View at Publisher · View at Google Scholar · View at Scopus
  99. V. B. Dorfman, L. Pasquini, M. Riudavets et al., “Differential cerebral deposition of IDE and NEP in sporadic and familial Alzheimer's disease,” Neurobiology of Aging, vol. 31, no. 10, pp. 1743–1757, 2010. View at Publisher · View at Google Scholar · View at Scopus
  100. O. Tanja, P. Facchinetti, C. Rose, M. C. Bonhomme, C. Gros, and J. C. Schwartz, “Neprilysin II: a putative novel metalloprotease and its isoforms in CNS and testis,” Biochemical and Biophysical Research Communications, vol. 271, no. 3, pp. 565–570, 2000. View at Publisher · View at Google Scholar · View at Scopus
  101. K. Ikeda, N. Emoto, S. B. Raharjo et al., “Molecular identification and characterization of novel membrane-bound metalloprotease, the soluble secreted form of which hydrolyzes a variety of vasoactive peptides,” The Journal of Biological Chemistry, vol. 274, no. 45, pp. 32469–32477, 1999. View at Publisher · View at Google Scholar · View at Scopus
  102. P. Facchinetti, C. Rose, J. C. Schwartz, and T. Ouimet, “Ontogeny, regional and cellular distribution of the novel metalloprotease neprilysin 2 in the rat: a comparison with neprilysin and endothelin-converting enzyme-1,” Neuroscience, vol. 118, no. 3, pp. 627–639, 2003. View at Publisher · View at Google Scholar · View at Scopus
  103. J. Y. Huang, A. M. Bruno, C. A. Patel et al., “Human membrane metallo-endopeptidase-like protein degrades both β-amyloid 42 and β-amyloid 40,” Neuroscience, vol. 155, no. 1, pp. 258–262, 2008. View at Publisher · View at Google Scholar · View at Scopus
  104. D. Hafez, J. Y. Huang, A. M. Huynh et al., “Neprilysin-2 is an important β-amyloid degrading enzyme,” American Journal of Pathology, vol. 178, no. 1, pp. 306–312, 2011. View at Publisher · View at Google Scholar · View at Scopus
  105. J. Y. Huang, D. M. Hafez, B. D. James et al., “Altered NEP2 expression and activity in mild cognitive impairment and Alzheimer's disease,” Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 433–441, 2012. View at Google Scholar
  106. B. Spencer, R. A. Marr, R. Gindi et al., “Peripheral delivery of a CNS targeted, metalo-protease reduces Aβ toxicity in a mouse model of Alzheimer's disease,” PLoS ONE, vol. 6, no. 1, Article ID e16575, 2011. View at Publisher · View at Google Scholar · View at Scopus
  107. Y. Li, J. Wang, J. Liu, and F. Liu, “A novel system for in vivo neprilysin gene delivery using a syringe electrode,” Journal of Neuroscience Methods, vol. 193, no. 2, pp. 226–231, 2010. View at Publisher · View at Google Scholar · View at Scopus
  108. M. L. Hemming, M. Patterson, C. Reske-Nielsen, L. Lin, O. Isacson, and D. J. Selkoe, “Reducing amyloid plaque burden via ex vivo gene delivery of an Aβ-degrading protease: a novel therapeutic approach to Alzheimer disease,” PLoS Medicine, vol. 4, no. 8, article e262, 2007. View at Publisher · View at Google Scholar · View at Scopus
  109. R. Deane, Z. Wu, and B. V. Zlokovic, “RAGE (Yin) versus LRP (Yang) balance regulates Alzheimer amyloid β-peptide clearance through transport across the blood-brain barrier,” Stroke, vol. 35, no. 11, pp. 2628–2631, 2004. View at Publisher · View at Google Scholar · View at Scopus
  110. Y. Liu, H. Guan, T. L. Beckett et al., “In vitro and in vivo degradation of Aβ peptide by peptidases coupled to erythrocytes,” Peptides, vol. 28, no. 12, pp. 2348–2355, 2007. View at Publisher · View at Google Scholar · View at Scopus
  111. H. Guan, Y. Liu, A. Daily et al., “Peripherally expressed neprilysin reduces brain amyloid burden: a novel approach for treating Alzheimer's disease,” Journal of Neuroscience Research, vol. 87, no. 6, pp. 1462–1473, 2009. View at Publisher · View at Google Scholar · View at Scopus
  112. Y. Liu, C. Studzinski, T. Beckett, M. P. Murphy, R. L. Klein, and L. B. Hersh, “Circulating neprilysin clears brain amyloid,” Molecular and Cellular Neuroscience, vol. 45, no. 2, pp. 101–107, 2010. View at Publisher · View at Google Scholar · View at Scopus
  113. S. S. El-Amouri, H. Zhu, J. Yu, R. Marr, I. M. Verma, and M. S. Kindy, “Neprilysin: an enzyme candidate to slow the progression of Alzheimer's disease,” American Journal of Pathology, vol. 172, no. 5, pp. 1342–1354, 2008. View at Publisher · View at Google Scholar · View at Scopus
  114. M. F. Melzig and M. Janka, “Enhancement of neutral endopeptidase activity in SK-N-SH cells by green tea extract,” Phytomedicine, vol. 10, no. 6-7, pp. 494–498, 2003. View at Publisher · View at Google Scholar · View at Scopus
  115. A. Kiss, J. Kowalski, and M. F. Melzig, “Effect of Epilobium angustifolium L. extracts and polyphenols on cell proliferation and neutral endopeptidase activity in selected cell lines,” Pharmazie, vol. 61, no. 1, pp. 66–69, 2006. View at Google Scholar · View at Scopus
  116. T. Sãito, N. Iwata, S. Tsubuki et al., “Somatostatin regulates brain amyloid β peptide Aβ42 through modulation of proteolytic degradation,” Nature Medicine, vol. 11, no. 4, pp. 434–439, 2005. View at Publisher · View at Google Scholar · View at Scopus
  117. T. Niikura, E. Sidahmed, C. Hirata-Fukae, P. S. Aisen, and Y. Matsuoka, “A humanin derivative reduces amyloid beta accumulation and ameliorates memory deficit in triple transgenic mice,” PLoS ONE, vol. 6, no. 1, Article ID e16259, 2011. View at Publisher · View at Google Scholar · View at Scopus
  118. S. Kalinin, J. C. Richardson, and D. L. Feinstein, “A PPARdelta agonist reduces amyloid burden and brain inflammation in a transgenic mouse model of Alzheimer's disease,” Current Alzheimer Research, vol. 6, no. 5, pp. 431–437, 2009. View at Publisher · View at Google Scholar · View at Scopus
  119. R. Pardossi-Piquard, A. Petit, T. Kawarai et al., “Presenilin-dependent transcriptional control of the Aβ-degrading enzyme neprilysin by intracellular domains of βAPP and APLP,” Neuron, vol. 46, no. 4, pp. 541–554, 2005. View at Publisher · View at Google Scholar · View at Scopus
  120. C. Yu, S. H. Kim, T. Ikeuchi et al., “Characterization of a presenilin-mediated amyloid precursor protein carboxyl-terminal fragment γ: evidence for distinct mechanisms involved in γ-secretase processing of the APP and Notch1 transmembrane domains,” The Journal of Biological Chemistry, vol. 276, no. 47, pp. 43756–43760, 2001. View at Publisher · View at Google Scholar · View at Scopus
  121. T. Sato, N. Dohmae, Y. Qi et al., “Potential link between amyloid β-protein 42 and C-terminal fragment γ 49–99 of β-amyloid precursor protein,” The Journal of Biological Chemistry, vol. 278, no. 27, pp. 24294–20301, 2003. View at Publisher · View at Google Scholar · View at Scopus
  122. A. C. Chen and D. J. Selkoe, “Response to: Pardossi-Piquard etal., “Presenilin-dependent transcriptional control of the Aβ-degrading enzyme neprilysin by intracellular domains of βAPP and APLP.” Neuron 46, 541–554,” Neuron, vol. 53, no. 4, pp. 479–483, 2007. View at Publisher · View at Google Scholar · View at Scopus
  123. S. S. Hébert, L. Serneels, A. Tolia et al., “Regulated intramembrane proteolysis of amyloid precursor protein and regulation of expression of putative target genes,” EMBO Reports, vol. 7, no. 7, pp. 739–745, 2006. View at Publisher · View at Google Scholar · View at Scopus
  124. E. Waldron, S. Isbert, A. Kern et al., “Increased AICD generation does not result in increased nuclear translocation or activation of target gene transcription,” Experimental Cell Research, vol. 314, no. 13, pp. 2419–2433, 2008. View at Publisher · View at Google Scholar · View at Scopus
  125. N. D. Belyaev, N. N. Nalivaeva, N. Z. Makova, and A. J. Turner, “Neprilysin gene expression requires binding of the amyloid precursor protein intracellular domain to its promoter: implications for Alzheimer disease,” EMBO Reports, vol. 10, no. 1, pp. 94–100, 2009. View at Publisher · View at Google Scholar · View at Scopus
  126. N. D. Belyaev, K. A. B. Kellett, C. Beckett et al., “The transcriptionally active amyloid precursor protein (APP) intracellular domain is preferentially produced from the 695 isoform of APP in a β-secretase-dependent pathway,” The Journal of Biological Chemistry, vol. 285, no. 53, pp. 41443–41454, 2010. View at Publisher · View at Google Scholar · View at Scopus
  127. C. Bauer, R. Pardossi-Piquard, J. Dunys et al., “β-secretase-mediated regulation of neprilysin: influence of cell density and aging and modulation by Imatinib,” Journal of Alzheimer's Disease, vol. 27, no. 3, pp. 511–520, 2011. View at Google Scholar
  128. Y. Hong, C. Beckett, N. D. Belyaev, and A. J. Turner, “The impact of amyloid precursor protein signalling and histone deacetylase inhibition on neprilysin expression in human prostate cells,” International Journal of Cancer, vol. 130, no. 4, pp. 775–786, 2012. View at Publisher · View at Google Scholar · View at Scopus
  129. Z. V. Goodger, L. Rajendran, A. Trutzel, B. M. Kohli, R. M. Nitsch, and U. Konietzko, “Nuclear signaling by the APP intracellular domain occurs predominantly through the amyloidogenic processing pathway,” Journal of Cell Science, vol. 122, no. 20, pp. 3703–3714, 2009. View at Publisher · View at Google Scholar · View at Scopus
  130. D. Aydin, M. A. Filippov, J. A. Tschäpe et al., “Comparative transcriptome profiling of amyloid precursor protein family members in the adult cortex,” BMC Genomics, vol. 12, article 160, 2011. View at Publisher · View at Google Scholar · View at Scopus
  131. R. Pardossi-Piquard and F. Checler, “The physiology of the β-amyloid precursor protein Intracellular domain AICD,” Journal of Neurochemistry, vol. 120, supplement 1, pp. 109–124, 2012. View at Publisher · View at Google Scholar
  132. X. Xu, H. Zhou, and T. G. Boyer, “Mediator is a transducer of amyloid-precursor-protein-dependent nuclear signalling,” EMBO Reports, vol. 12, no. 3, pp. 216–222, 2011. View at Publisher · View at Google Scholar · View at Scopus
  133. A. J. Turner, N. D. Belyaev, and N. N. Nalivaeva, “Mediator: the missing link in amyloid precursor protein nuclear signalling,” EMBO Reports, vol. 12, no. 3, pp. 180–181, 2011. View at Publisher · View at Google Scholar · View at Scopus
  134. H. Qing, G. He, P. T. T. Ly et al., “Valproic acid inhibits Aβ production, neuritic plaque formation, and behavioral deficits in Alzheimer's disease mouse models,” Journal of Experimental Medicine, vol. 205, no. 12, pp. 2781–2789, 2008. View at Publisher · View at Google Scholar · View at Scopus
  135. N. N. Nalivaeva, N. D. Belyaev, and A. J. Turner, “Sodium valproate: an old drug with new roles,” Trends in Pharmacological Sciences, vol. 30, no. 10, pp. 509–514, 2009. View at Publisher · View at Google Scholar · View at Scopus
  136. M. Kilgore, C. A. Miller, D. M. Fass et al., “Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer's disease,” Neuropsychopharmacology, vol. 35, no. 4, pp. 870–880, 2010. View at Publisher · View at Google Scholar · View at Scopus
  137. Y. S. Eisele, M. Baumann, B. Klebl, C. Nordhammer, M. Jucker, and E. Kilger, “Gleevec increases levels of the amyloid precursor protein intracellular domain and of the amyloid-β degrading enzyme neprilysin,” Molecular Biology of the Cell, vol. 18, no. 9, pp. 3591–3600, 2007. View at Publisher · View at Google Scholar · View at Scopus
  138. M. C. Vázquez, L. M. Vargas, N. C. Inestrosa, and A. R. Alvarez, “C-Abl modulates AICD dependent cellular responses: transcriptional induction and apoptosis,” Journal of Cellular Physiology, vol. 220, no. 1, pp. 136–143, 2009. View at Publisher · View at Google Scholar · View at Scopus
  139. B. A. Usmani, R. Shen, M. Janeczko et al., “Methylation of the neutral endopeptidase gene promoter in human prostate cancers,” Clinical Cancer Research, vol. 6, no. 5, pp. 1664–1670, 2000. View at Google Scholar · View at Scopus
  140. J. Dai, R. Shen, M. Sumitomo et al., “Tumor-suppressive effects of neutral endopeptidase in androgen-independent prostate cancer cells,” Clinical Cancer Research, vol. 7, no. 5, pp. 1370–1377, 2001. View at Google Scholar · View at Scopus
  141. E. Hama and T. C. Saido, “Etiology of sporadic Alzheimer's disease: somatostatin, neprilysin, and amyloid β peptide,” Medical Hypotheses, vol. 65, no. 3, pp. 498–500, 2005. View at Publisher · View at Google Scholar · View at Scopus