Neurochemical Research

, Volume 32, Issue 12, pp 2062–2071 | Cite as

Brain-Specific Aminopeptidase: From Enkephalinase to Protector Against Neurodegeneration

Original Paper


The major breakthrough discovery of enkephalins as endogenous opiates led our attempts to determine their inactivation mechanisms. Because the NH2-terminal tyrosine is absolutely necessary for the neuropeptides to exert analgesic effects, and aminopeptidase activities are extraordinarily high in the brain, a specific “amino-enkephalinase” should exist. Several aminopeptidases were identified in the central nervous system during the search. In fact, our laboratory found two novel neuron-specific aminopeptidases: NAP and NAP-2. NAP is the only functionally active brain-specific enzyme known. Its synaptic location coupled with its limited substrate specificity could constitute a “functional” specificity and contribute to enkephalin-specific functions. In addition, NAP was found to be essential for neuron growth, differentiation, and death. Thus, aminopeptidases are likely important for mental health and neurological diseases. Recently, puromycin-sensitive aminopeptidase (PSA) was identified as a modifier of tau-induced neurodegeneration. Because the enzymatic similarity between PSA and NAP, we believe that the depletion of NAP in Alzheimer’s disease (AD) brains plays a causal role in the development of AD pathology. Therefore, use of the puromycin-sensitive neuron-aminopeptidase NAP could provide neuroprotective mechanisms in AD and similar neurodegenerative diseases.


Neuron-specific aminopeptidase Neuropeptides Enkephalins Neurodegeneration Alzheimer’s disease 


  1. 1.
    Hui K-S, Lajtha A (1983) Neuropeptides. In: Lajtha A (ed) Handbook of neurochemistry, 2nd edn., vol. 4. Plenum, New York, pp 1–19Google Scholar
  2. 2.
    Taylor A (1993) Aminopeptidases: structure and function. FASEB J 7:290–298PubMedGoogle Scholar
  3. 3.
    Taylor A (1993) Aminopeptidases: towards a mechanism of action. Trends Biochem Sci 18:167–171PubMedGoogle Scholar
  4. 4.
    Yao T, Cohen RE (1999) Giant proteases: beyond the proteasome. Curr Biol 9: R551–R553PubMedCrossRefGoogle Scholar
  5. 5.
    Lendeckel U, Arndt M, Frank K, Spiess A, Reinhold D, Ansorge S (2000) Modulation of WNT-5A expression by actinonin: linkage of APN to the WNT-pathway? Adv Exp Med Biol 477:35–41PubMedGoogle Scholar
  6. 6.
    Stoltze L, Schirle M, Schwarz G, Schroter C, Thompson MW, Hersh LB, Kalbacher H, Stevanovic S, Rammensee HG, Schild H (2000) Two new proteases in the MHC class I processing pathway. Nat Immunol 1:413–418PubMedCrossRefGoogle Scholar
  7. 7.
    Hui K-S (2007) Neuropeptidases. In: Lajtha A, Banik NL (eds), Handbook of neurochemistry and molecular neurobiology: neural protein metabolism and function, 3rd edn., vol. 7. Springer-Verlag, Berlin, HeidelbergGoogle Scholar
  8. 8.
    Nakanish S, Inoue A, Kita T, Nakamura M, Chang ACY, Cohen SN, Numa S (1979) Nucleotide sequence of cloned cDNA for bovine corticotropin-β-lipotropin precursor. Nature 278:423–424CrossRefGoogle Scholar
  9. 9.
    Gubler U, Seeburg P, Hoffman BJ, Gage LP, Udenfriend S (1982) Molecular cloning establishes proenkephalin as precursor of enkephalin-containing peptides. Nature 295:206–208PubMedCrossRefGoogle Scholar
  10. 10.
    Boileu G, Barbeau C, Jeannotte L, Chretien M, Drouin J (1983) Complete structure of the porcine proopiomelanocortin mRNA derived from the nucleotide sequence of cloned cDNA. Nucleic Acids Res 11:8063–8071CrossRefGoogle Scholar
  11. 11.
    Yoshikawa K, Williams C, Sabol SL (1984) Rat brain preproenkephalin mRNA, cDNA cloning, primary structure, and distribution in the central nervous system. J Biol Chem 259:14301–14308PubMedGoogle Scholar
  12. 12.
    Civelli O, Douglass J, Goldstein A, Herbert E (1985) Sequence and expression of the rat prodynorphin gene. Proc Natl Acad Sci USA 82:4291–4295PubMedCrossRefGoogle Scholar
  13. 13.
    Nothacker HP, Reinschied RK, Mansour A, Henningsen RA, Ardati A, Monsma FJ, Watson SJ, Civelli O (1996) Primary structure and tissue distribution of the orphanin FQ precursor. Proc Natl Acad Sci USA 93:8677–8682PubMedCrossRefGoogle Scholar
  14. 14.
    Molleraeu C, Simons MJ, Soulariue P, Liners F, Vassart G, Meunier JC, Parmentier M (1996) Structure tissue distribution and chromosomal localization of the prepronociceptin gene. Proc Natl Acad Sci USA 93:8666–8670CrossRefGoogle Scholar
  15. 15.
    Hook VYH, Reisine TD (2001) Endorphin. In: Creighton TE (ed) Encyclopedia of molecular medicine, pp 1161–1164Google Scholar
  16. 16.
    Frenk H, McCarty BC, Lieberkind JC (1978) Different brain areas mediate the analgesic and epileptic properties of enkephalin. Science 200:335–337PubMedCrossRefGoogle Scholar
  17. 17.
    Lee JJ, Hahm ET, Min BI, Cho YW (2004) Activation of protein kinase C antagonizes the opioid inhibition of calcium current in rat spinal dorsal horn neurons. Brain Res 1017:108–119PubMedCrossRefGoogle Scholar
  18. 18.
    De Wied D, Bohus B, van Ree JM, Urban I (1978) Behavioral and electrophysiological effects of peptides related to lipotropin (β-LPH) J. Pharmacol Exp Ther 204:570–580Google Scholar
  19. 19.
    Holaday JH, Loh HH, Li CH (1978) Unique behavioral effects of β-endorphin and their relationship to thermoregulation and hypothalamic function. Life Sci 22:1525–1536PubMedCrossRefGoogle Scholar
  20. 20.
    Brands B, Thornhill JB, Hirst M, Gowdey CW (1979) Suppression of food intake and body weight gain by naloxone in rats. Life Sci 24:1773–1778PubMedCrossRefGoogle Scholar
  21. 21.
    Meyerson BJ, Terenius L (1977) β-endorphin and male sexual behavior. Eur J Pharmacol 42:191–192PubMedCrossRefGoogle Scholar
  22. 22.
    Morley JE. 1981. The endocrinology of the opiates and opioid peptides. Metabolism 30:195–209PubMedCrossRefGoogle Scholar
  23. 23.
    Bloom F, Segal D, Ling N, Guillemin R (1976) Endorphins: profound behavioral effects in rats suggest new etiological factors in mental illness. Science 194:630–632PubMedCrossRefGoogle Scholar
  24. 24.
    Jacquet YF, Marks N (1976) The C-fragment of β-lipotropin: an endogenous neuroleptic or antipsychotogen? Science 194:632–635PubMedCrossRefGoogle Scholar
  25. 25.
    Matsuzaki S, Ikeda H, Akiyama G, Sato M, Moribe S, Suzuki T, Nagase H, Cools AR, Koshikawa N (2004) Role of mu- and delta-opioid receptors in the nucleus accumbens in turning behaviour of rats. Neuropharmacology 46:1089–1096PubMedCrossRefGoogle Scholar
  26. 26.
    Goodman RR, Fricker LD, Snyder SH (1983) Enkephalins. In: Krieger DT, Brownstein MJ, Martin JB (eds) Brain peptides. John Wiley & Sons, New York, pp 827–849Google Scholar
  27. 27.
    Patey G, De La Baume S, Schwartz J-C, Gros C, Roques B-P, Fournie-Zaluski M-C, Soroca-Lucas E (1981) Selective protection of methionine enkephalin release from brain slices by enkephalinase inhibition. Science 212:1153–1155PubMedCrossRefGoogle Scholar
  28. 28.
    Schwartz J-C (1983) Metabolism of enkephalins and the inactivating neuropeptidase concept. Trends Neurosci 6:15–18CrossRefGoogle Scholar
  29. 29.
    Lee C-M, Snyder SH (1982) Dipeptidyl-aminopeptidase III of rat brain. J Biol Chem 257:12043–12050PubMedGoogle Scholar
  30. 30.
    Horsthemke B, Hamprecht B., Bauer K (1983) Heterogeneous distribution of enkephalin-degrading peptidases between neuronal and glial cells. Biochem Biophys Res Comm 115:423–429PubMedCrossRefGoogle Scholar
  31. 31.
    Llorens C, Cacel G, Swerts J-P, Perdrisot R, Fournie-Zaluski K-C, Schwartz J-C, Roques B-P (1980) Rational design of enkephalinase inhibitor: substrate specificity of enkephalinase studied from inhibitory potency of various dipeptides. Biochem Biophys Res Commun 96:1710–1716PubMedCrossRefGoogle Scholar
  32. 32.
    Barnes K, Turner AJ, Kenny AJ (1988) Electronmicroscopic immunocytochemistry of pig brain shows that endopeptidase 24.11 is localized in neuronal membranes. Neurosci Lett 94:64–69PubMedCrossRefGoogle Scholar
  33. 33.
    Skidgel RA, Erdos EG (2004) Angiotensin-converting enzyme (ACE) and neprilysin hydrolyze neuropeptides: a brief history, the beginning and follow-ups to early studies. Peptides 25:521–525PubMedCrossRefGoogle Scholar
  34. 34.
    Howell S, Murray H, Scott CS, Turner AJ, Kenny AJ (1991) A highly sensitive EL.IS.A. for endopeptidase-24.11, the common acute-lymphoblastic-leukaemia antigen (CALLA, CD-10), applicable to material of porcine and human origin. Biochem J 278:417–421PubMedGoogle Scholar
  35. 35.
    Knight M, Klee WA (1978) The relationship between enkephalin degradation and opiate receptor occupancy. J Biol Chem 253:3843–3847PubMedGoogle Scholar
  36. 36.
    Cox BM (1982) Endogenous opioid peptides: a guide to structures and terminology. Life Sci 31:1645–1658PubMedCrossRefGoogle Scholar
  37. 37.
    Amar C, Vilkas E, Laurent S, Gautray B, Schmitt H (1983) A new enkephalin analogue: trans-4-hydroxycinnamoyl-glycyl-glycyl-phenylalanyl-leucine synthesis and biological properties. Int J Peptide Protein Res 22:434–436CrossRefGoogle Scholar
  38. 38.
    Lentzen H., Palenker J (1983) Localization of the thiorphan-sensitive endopeptidase, termed enkephalinase A, on glial cells. FEBS Lett 153:93–97PubMedCrossRefGoogle Scholar
  39. 39.
    Schwartz J-C, Costentin J, Lecomte J-M (1985) Pharmacology of enkephalinase inhibitors. Trends Pharmacol Sci 6:472–476CrossRefGoogle Scholar
  40. 40.
    Zhang A-Z, Yang H-Y, Costa E (1982) Nociception enkephalin content and dipeptidyl carboxypeptidase activity in brain of mice treated with exopeptidase inhibitors. Neuropharmacol 21:625–630CrossRefGoogle Scholar
  41. 41.
    De La Baume S. Yi CC, Schwartz J-C, Marcais-Collado H, Costentin J (1983) Participation of both “enkephalinase” and aminopeptidase activities in the metabolism of endogenous enkephalins. Neurosci 8:143–151CrossRefGoogle Scholar
  42. 42.
    Herman ZS,Strachura Z, Laskawiec G, Kowalski J, Obuchowicz E (1985) Antinociceptive effects of puromycin and bacitracin. Pol J Pharmacol 37:133–140Google Scholar
  43. 43.
    Look AT, Ashmun RA, Shapiro LH, Peiper SC (1989) Human myeloid plasma membrane glycoprotein CD13 (gp150) is identical to aminopeptidase. N J Clin Invest 83:1299–1307Google Scholar
  44. 44.
    Razak K, Newland AC (1992) Induction of CD13 expression on fresh myeloid leukaemia: correlation of CD13 expression with aminopeptidase-N activity. Leuk Res 16:625–630PubMedCrossRefGoogle Scholar
  45. 45.
    Hersh LB, Aboukhair N, Watson S (1987) Immunohistochemical localization of aminopeptidase M in rat brain and periphery: relationship of enzyme localization and enkephalin metabolism. Peptides 8:523–532PubMedCrossRefGoogle Scholar
  46. 46.
    McLellan S, Dyer SH, Rodriguez G, Hersh LB (1988) Studies on the tissue distribution of the puromycin-sensitive enkephalin-degrading aminopeptidases. J Neurochem 51:1552–1559PubMedCrossRefGoogle Scholar
  47. 47.
    Dyer SH, Slaughter CA, Orth K, Moomaw CR, Hersh LB (1990) Comparison of the soluble and membrane-bound forms of the puromycin-sensitive enkephalin-degrading aminopeptidases from rat. J Neurochem 54:547–554PubMedCrossRefGoogle Scholar
  48. 48.
    Tobler AR, Constam DB, Schmitt-Graff A, Malipiero U, Schlapbach R, Fontana A (1997) Cloning of the human puromycin-sensitive aminopeptidase and evidence for expression in neuron. J Neurochem 68:889–897PubMedCrossRefGoogle Scholar
  49. 49.
    Thompson MW, Tobler A, Fontana A, Hersh LB (1999) Cloning and analysis of the gene for the human puromycin-sensitive aminopeptidase. Biochem Biophys Res Commun 258:234–240PubMedCrossRefGoogle Scholar
  50. 50.
    Brooks DR, Hooper NM, Isaac RE (2003) The Caenorhabditis elegans orthologue of mammalian puromycin-sensitive aminopeptidase has roles in embryogenesis and reproduction. J Biol Chem 278:42795–42801PubMedCrossRefGoogle Scholar
  51. 51.
    Roques BP (1985) Enkephalinase inhibitors and molecular exploration of the differences between active sites of enkephalinase and the angiotensin conversion enzyme. J Pharmacol (Paris) 16:5–31Google Scholar
  52. 52.
    Osada T, Ikegami S, Takiguchi-Hayashi K, Yamazaki Y, Katoh-Fukui Y, Higashinakagawa T, Sakaki Y, Takeuchi T (1999) Increased anxiety and impaired pain response in puromycin-sensitive aminopeptidase gene-deficient mice obtained by a mouse gene-trap method. J Neurosci 19:6068–6078PubMedGoogle Scholar
  53. 53.
    Osada T, Watanabe G, Kondo S, Toyoda M, Sakaki Y, Takeuchi T (2001) Male reproductive defects caused by puromycin-sensitive aminopeptidase deficiency in mice. Mol Endocrinol 15:960–971PubMedCrossRefGoogle Scholar
  54. 54.
    Konig M, Zimmer AM, Steiner H, Holmes PV, Crawley J, Brownstein MJ, Simmer A (1996) Pain responses anxiety and aggression in mice deficient in pre-enkephalin. Nature 383:535–538PubMedCrossRefGoogle Scholar
  55. 55.
    Thompson MW Govindaswami M, Hersh LB (2003) Mutation of active site residues of the puromycin-sensitive aminopeptidase: conversion of the enzyme into a catalytically inactive binding protein. Arch Biochem Biophys 413:236–242CrossRefGoogle Scholar
  56. 56.
    Wilce MCJ, Bond CS, Dixon NE, Freeman HC, Guss JM, Lilley PE, Wilce JA (1998) Structure and mechanism of a proline-specific aminopeptidase from Escherichia coli. Proc Nat Acad Sci USA 95:3472–3477PubMedCrossRefGoogle Scholar
  57. 57.
    Thunnissen MMGM, Nordlund P, Haeggström JZ (2001) Crystal structure of human leukotrine A4 hydrolyse, a bifunctional enzyme in inflammation. Nat Struct Biol 8:131–135PubMedCrossRefGoogle Scholar
  58. 58.
    Wei L, Alhenc-Gelas F, Corvol P, Clauser E (1991) The two homologous domains of human angiotensin I-converting enzyme are both catalytically active. J Biol Chem 266:9002–9008PubMedGoogle Scholar
  59. 59.
    Shen Y, Joachimiak A, Rosner MR, Tang W-J (2006) Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism. Nature 443:870–874PubMedCrossRefGoogle Scholar
  60. 60.
    Johnson GD, Hersh LB (1990) Studies on the subsite specificity of the rat brain puromycin-sensitive aminopeptidase. Arch Biochem Biophys 276:305–309PubMedCrossRefGoogle Scholar
  61. 61.
    Hui K-S, Hui M, Lajtha A (1983) Properties of a brain membrane aminoenkephalinase: inhibition studies. In: Sun G, Bazan N, Wu J-Y, Porcellati G, Sun AY (eds) Neural membranes. Humana Press, NJ, pp 375–393Google Scholar
  62. 62.
    Turner AJ, Murphy LJ, Medeios MS, Barnes K (1996) Endopeptidase-24.11(neprilysin) and relatives: twenty years on. Adv Exptl Med Biol 389:141–148Google Scholar
  63. 63.
    Constam DB, Tobler AR, Rensing-Ehl A, Kemler I, Hersh LB, Fontana A (1995) Puromycin-sensitive aminopeptidase: sequence analysis, expression, and functional characterization. J Biol Chem 270:26931–26939PubMedCrossRefGoogle Scholar
  64. 64.
    Sekine K, Fujii H, Abe F (1999) Induction of apoptosis by bestatin (ubenimex) in human leukemic cell lines. Leukemia 13:729–734PubMedCrossRefGoogle Scholar
  65. 65.
    Schulz C, Perezgasga L, Fuller MT (2001) Genetic analysis of dPSA, the Drosophila orthologue of puromycin-sensitive aminopeptidase, suggests redundancy of aminopeptidases. Dev Genes Evol 211:581–588PubMedCrossRefGoogle Scholar
  66. 66.
    Hui M, Palkovits M, Lajtha A, Budai D, Hui K-S (1995) Changes in puromycin-sensitive aminopeptidase in postmortem schizophrenic brain regions. Neurochem Int 27:433–441PubMedCrossRefGoogle Scholar
  67. 67.
    Schonlein C, Loffler J, Huber G (1994) Purification and characterization of a novel metalloprotease from human brain with the ability to cleave substrates derived from the N-terminus of beta-amyloid protein. Biochem Biophys Res Commun 201:45–53PubMedCrossRefGoogle Scholar
  68. 68.
    Minnasch P, Yamamoto Y, Ohkubo I, Nishi K (2003) Demonstration of puromycin-sensitive alanyl aminopeptidase in Alzheimer disease brain. Leg Med (Tokyo) 5 (supply 1): S285–S287Google Scholar
  69. 69.
    Ingram EM, Spillantini MG (2002) Tau gene mutations: dissecting the pathogenesis of FTDP-17. Trends Mol Med 8:555–562PubMedCrossRefGoogle Scholar
  70. 70.
    Lee VM, Goedert M, Trojanowski JQ (2001) Neurodegenerative tauopathies. Annu Rev Neurosci 24:1121–1159PubMedCrossRefGoogle Scholar
  71. 71.
    Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, de Graaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Che LK, Norton J, Morris JC, Reed LA, Trojanowski J, Basun H, Lannfelt L, Neystat M, Fahn S, Dark F, Tannenberg T, Dodd PR, Hayward N, Kwok JB, Schofield PR, Andreadis A, Snowden J, Craufurd D, Neary D, Owen F, Oostra BA, Hardy J, Goate A, van Swieten J, Mann D, Lynch T, Heutink P (1998) Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393:702–705PubMedCrossRefGoogle Scholar
  72. 72.
    Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI (1986) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 83:4913–4917PubMedCrossRefGoogle Scholar
  73. 73.
    Kosik KS, Shimura H (2005) Phosphorylated tau and the neurodegenerative foldopathies. Biochim Biophys Acta 1739:298–310PubMedGoogle Scholar
  74. 74.
    Lee VM, Balin BJ, Otvos L Jr, Trojanowski JQ (1991) A68: a major subunit of paired helical filaments and derivatized forms of normal tau. Science 251:675–678PubMedCrossRefGoogle Scholar
  75. 75.
    Gamblin TC, Chen F, Zambrano A, Abraha A, Lagalwar S, Guillozet AL, Lu M, Fu Y, Garcia-Sierra F, LaPointe N, Miller R, Berry RW, Binder LI, Cryns VL (2003) Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer’s disease. Proc Natl Acad Sci USA 100:10032–10037PubMedCrossRefGoogle Scholar
  76. 76.
    Bancher C, Grundke-Iqbal I, Iqbal K, Fried VA, Smith HT, Wisniewski HM (1991) Abnormal phosphorylation of tau precedes ubiquitination in neurofibrillary pathology of Alzheimer disease. Brain Res 539:11–18PubMedCrossRefGoogle Scholar
  77. 77.
    Gong CX, Liu F, Grundke-Iqbal I, Iqbal K (2005) Posttranslational modifications of tau protein in Alzheimer’s disease. J Neural Transm 112:813–838PubMedCrossRefGoogle Scholar
  78. 78.
    Iqbal K, Grundke-Iqbal I (1991) Ubiquitination and abnormal phosphorylation of paired helical filaments in Alzheimer’s disease. Mol Neurobiol 5:399–410PubMedCrossRefGoogle Scholar
  79. 79.
    Liu F, Zaidi T, Iqbal K, Grundke-Iqbal I, Merkle RK, Gong CX (2002) Role of glycosylation in hyperphosphorylation of tau in Alzheimer’s disease. FEBS Lett 512:101–106PubMedCrossRefGoogle Scholar
  80. 80.
    Wang JZ, Grundke-Iqbal I, Iqbal K (1996) Glycosylation of microtubule-associated protein tau: an abnormal posttranslational modification in Alzheimer’s disease. Nat Med 2:871–875PubMedCrossRefGoogle Scholar
  81. 81.
    Amadoro G, Serafino AL, Barbato C, Ciotti MT, Sacco A, Calissano P, Canu N (2004) Role of N-terminal tau domain integrity on the survival of cerebellar granule neurons. Cell Death Differ 11:217–230PubMedCrossRefGoogle Scholar
  82. 82.
    Chen F, David D, Ferrari A, Gotz J (2004) Posttranslational modifications of tau–role in human tauopathies and modeling in transgenic animals. Curr Drug Targets 5:503–515PubMedCrossRefGoogle Scholar
  83. 83.
    Arai T, Guo JP, McGeer PL (2005) Proteolysis of nonphosphorylated and phosphorylated tau by thrombin. J Biol Chem 280:5145–5153PubMedCrossRefGoogle Scholar
  84. 84.
    Mercken M, Grynspan F, Nixon RA (1995) Differential sensitivity to proteolysis by brain calpain of adult human tau, fetal human tau and PHF-tau. FEBS Lett 368:10–14PubMedCrossRefGoogle Scholar
  85. 85.
    Kosik KS, Ahn J, Stein R, Yeh LA (2002) Discovery of compounds that will prevent tau pathology. J Mol Neurosci 19:261–266PubMedCrossRefGoogle Scholar
  86. 86.
    Price DL, Tanzi RE, Borchelt DR, Sisodia SS (1998) Alzheimer’s disease: genetic studies and transgenic models. Annu Rev Genet 32:461–493PubMedCrossRefGoogle Scholar
  87. 87.
    Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, Guimaraes A, DeTure M, Ramsden M, McGowan E, Forster C, Yue M, Orne J, Janus C, Mariash A, Kuskowski M, Hyman B, Hutton M, Ashe KH (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309:476–481PubMedCrossRefGoogle Scholar
  88. 88.
    Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356PubMedCrossRefGoogle Scholar
  89. 89.
    Sisodia SS, St George-Hyslop PH (2002) Gamma-Secretase Notch, Abeta and Alzheimer’s disease: where do the presenilins fit in? Nat Rev Neurosci 3:281–290PubMedCrossRefGoogle Scholar
  90. 90.
    D′Souza I, Schellenberg GD (2005) Regulation of tau isoform expression and dementia. Biochim Biophys Acta 1739:104–115PubMedGoogle Scholar
  91. 91.
    Karsten SL, Sang T-K, Gehman LT, Chatterjee S, Liu J, Lawless GM, Sengupta S, Berry RW, Pomakian J, Oh HS, Schulz C, Hui K-S, Wiedau-Pazos M, Vinters HV, Binder LI, Geschwind DH, Jackson GR (2006) A genomic screen for modifiers of tauopathy identifies puromycin-sensitive aminopeptidase as an inhibitor of tau-Induced neurodegeneration. Neuron 51:549–560PubMedCrossRefGoogle Scholar
  92. 92.
    Sengupta S, Horowitz PM, Karsten SL, Jackson GR, Geschwind DH, Fu Y, Berry RW, Binder LI (2006) Degradation of Tau protein by puromycin-sensitive aminopeptidase in vitro. Biochemistry 45:15111–15119PubMedCrossRefGoogle Scholar
  93. 93.
    Springer AD, Agranoff BW (1976) Electroconvulsive shock––or puromycin––induced retention deficits in goldfish given two-avoidance sessions. Behav Biol 18:309–324PubMedCrossRefGoogle Scholar
  94. 94.
    Flexner JB, Flexner LB, Stellar E (1963) Memory in mice as affected by intracerebral puromycin. Science 141:57–59PubMedCrossRefGoogle Scholar
  95. 95.
    Eisenstein EM, Altman HJ, Barraco DA, Barraco RA, Lovell KL (1983) Brain protein synthesis and memory: the use of antibiotic probes. Fed Proc 42:3080–3085PubMedGoogle Scholar
  96. 96.
    Flexner LB, Gambetti P, Flexner JB, Roberts RB (1971) Studies on memory: distribution of peptidyl-puromycin in subcellular fractions of mouse brain. Proc Natl Acad Sci USA 68:26–28PubMedCrossRefGoogle Scholar
  97. 97.
    Hui M, Hui KS (2003) Neuron-specific aminopeptidase and puromycin-sensitive aminopeptidase in rat brain development. Neurochem Res 28:855–860PubMedCrossRefGoogle Scholar
  98. 98.
    Osada T, Watanabe G, Sakaki Y, Takeuchi T (2001) Puromycin-sensitive aminopeptidase is essential for the maternal recognition of pregnancy in mice. Mol Endocrinol 15:882–893PubMedCrossRefGoogle Scholar
  99. 99.
    Shaw SG, Cook WF (1978) Localization and characterisation of aminopeptidase in the CNS and the hydrolysis of enkephalin. Nature 274:816–817PubMedCrossRefGoogle Scholar
  100. 100.
    Hui K-S, Hui M (1996) An automatic continuous-flow aminopeptidase detector and its applications. Anal Biochem 242:271–273PubMedCrossRefGoogle Scholar
  101. 101.
    Hui K-S, Saito M, Hui M (1998) A novel neuron-specific aminopeptidase in Rat brain synaptosomes: its identification, purification, and characterization. J Biol Chem 273:31053–31060PubMedCrossRefGoogle Scholar
  102. 102.
    Shannon JD, Baramova EN, Bjarnason JB, Fox JW (1989) Amino acid sequence of a Crotalus atrox venom metalloproteinase which cleaves type IV collagen and gelatin. J Biol Chem 264:11575–11583PubMedGoogle Scholar
  103. 103.
    Hui M, Lajtha A, Hui K-S (1993) A new soluble brain-specific protein: identification and partial purification. Brain Res 606:36–43PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Peptide Research Laboratory, Neurochemistry DivisionNathan S. Kline Institute for Psychiatric ResearchOrangeburgUSA
  2. 2.Department of PsychiatryNew York University Medical SchoolNew YorkUSA

Personalised recommendations