Acta Neuropathologica

, Volume 129, Issue 4, pp 541–563 | Cite as

Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system: new aspects on Alzheimer’s disease

  • Csaba ÁdoriEmail author
  • Laura Glück
  • Swapnali Barde
  • Takashi Yoshitake
  • Gabor G. Kovacs
  • Jan Mulder
  • Zsófia Maglóczky
  • László Havas
  • Kata Bölcskei
  • Nicholas Mitsios
  • Mathias Uhlén
  • János Szolcsányi
  • Jan Kehr
  • Annica Rönnbäck
  • Thue Schwartz
  • Jens F. Rehfeld
  • Tibor Harkany
  • Miklós Palkovits
  • Stefan Schulz
  • Tomas HökfeltEmail author
Original Paper


Alzheimer’s disease and other age-related neurodegenerative disorders are associated with deterioration of the noradrenergic locus coeruleus (LC), a probable trigger for mood and memory dysfunction. LC noradrenergic neurons exhibit particularly high levels of somatostatin binding sites. This is noteworthy since cortical and hypothalamic somatostatin content is reduced in neurodegenerative pathologies. Yet a possible role of a somatostatin signal deficit in the maintenance of noradrenergic projections remains unknown. Here, we deployed tissue microarrays, immunohistochemistry, quantitative morphometry and mRNA profiling in a cohort of Alzheimer’s and age-matched control brains in combination with genetic models of somatostatin receptor deficiency to establish causality between defunct somatostatin signalling and noradrenergic neurodegeneration. In Alzheimer’s disease, we found significantly reduced somatostatin protein expression in the temporal cortex, with aberrant clustering and bulging of tyrosine hydroxylase-immunoreactive afferents. As such, somatostatin receptor 2 (SSTR2) mRNA was highly expressed in the human LC, with its levels significantly decreasing from Braak stages III/IV and onwards, i.e., a process preceding advanced Alzheimer’s pathology. The loss of SSTR2 transcripts in the LC neurons appeared selective, since tyrosine hydroxylase, dopamine β-hydroxylase, galanin or galanin receptor 3 mRNAs remained unchanged. We modeled these pathogenic changes in Sstr2 −/− mice and, unlike in Sstr1 / or Sstr4 / genotypes, they showed selective, global and progressive degeneration of their central noradrenergic projections. However, neuronal perikarya in the LC were found intact until late adulthood (<8 months) in Sstr2 −/− mice. In contrast, the noradrenergic neurons in the superior cervical ganglion lacked SSTR2 and, as expected, the sympathetic innervation of the head region did not show any signs of degeneration. Our results indicate that SSTR2-mediated signaling is integral to the maintenance of central noradrenergic projections at the system level, and that early loss of somatostatin receptor 2 function may be associated with the selective vulnerability of the noradrenergic system in Alzheimer’s disease.


Alzheimer’s disease Co-existence Depression Neurodegeneration Neuropeptide Neurotransmitter Noradrenaline 



We are grateful for the excellent technical assistance of Blanca Silva-Lopez, Agnieszka Limiszweska and Anita Bergstrand. We thank Professor Tamas Freund, Laboratory of Cerebral Cortex Research, Institute of Experimental Medicine of the Hungarian Academy of Sciences, Budapest, Hungary for generous donation of human brain tissue. Thanks to Professors Staffan Cullheim, Department of Neuroscience, Karolinska Institutet, Stockholm and Bengt Winblad, Department of Neurobiology, Care Sciences and Society, Alzheimer Disease Research Center, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, Stockholm, for support, and to Dr. Zsolt Csaba (INSERM, Paris, France) and Dr. Szilvia Vas (Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary) for valuable discussions. Thanks to Professor Charles Glabe, Department of Molecular Biology and Biochemistry, University of California at Irvine, Irvine, CA, for generous donation of the OC antibody. This study was supported by the Swedish Research Council, Grants from Karolinska Institutet, the Knut and Lars Hiertas Minne Foundation, the Novo Nordisk Foundation, the Petrus and Augusta Hedlunds Foundation, the Alzheimerfonden (Grant 03-216) and the Hungarian National Brain Research Program (KTIA-NEP-13-1-2013-001).

Conflict of interest

The authors do not report any conflict of interest.

Ethical approval

All procedures performed in studies involving human tissue were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Supplementary material

401_2015_1394_MOESM1_ESM.docx (1.6 mb)
Supplementary material 1 (DOCX 1,648 kb)


  1. 1.
    Adams JC (1992) Biotin amplification of biotin and horseradish peroxidase signals in histochemical stains. J Histochem Cytochem 40:1457–1463PubMedGoogle Scholar
  2. 2.
    Adolfsson R, Gottfries CG, Roos BE, Winblad B (1979) Changes in the brain catecholamines in patients with dementia of Alzheimer type. Br J Psychiatry 135:216–223PubMedGoogle Scholar
  3. 3.
    Adori C, Ando RD, Szekeres M, Gutknecht L, Kovacs GG, Hunyady L, Lesch KP, Bagdy G (2011) Recovery and aging of serotonergic fibers after single and intermittent MDMA treatment in Dark Agouti rat. J Comp Neurol 519:2353–2378. doi: 10.1002/cne.22631 PubMedGoogle Scholar
  4. 4.
    Adori C, Low P, Ando RD, Gutknecht L, Pap D, Truszka F, Takacs J, Kovacs GG, Lesch KP, Bagdy G (2011) Ultrastructural characterization of tryptophan hydroxylase 2-specific cortical serotonergic fibers and dorsal raphe neuronal cell bodies after MDMA treatment in rat. Psychopharmacology 213:377–391. doi: 10.1007/s00213-010-2041-2 PubMedGoogle Scholar
  5. 5.
    Allen JP, Canty AJ, Schulz S, Humphrey PP, Emson PC, Young HM (2002) Identification of cells expressing somatostatin receptor 2 in the gastrointestinal tract of Sstr2 knockout/lacZ knockin mice. J Comp Neurol 454:329–340. doi: 10.1002/cne.10466 PubMedGoogle Scholar
  6. 6.
    Allen JP, Hathway GJ, Clarke NJ, Jowett MI, Topps S, Kendrick KM, Humphrey PP, Wilkinson LS, Emson PC (2003) Somatostatin receptor 2 knockout/lacZ knockin mice show impaired motor coordination and reveal sites of somatostatin action within the striatum. Eur J Neurosci 17:1881–1895PubMedGoogle Scholar
  7. 7.
    Armstrong DM, Hersh LB, Gage FH (1988) Morphologic alterations of cholinergic processes in the neocortex of aged rats. Neurobiol Aging 9:199–205PubMedGoogle Scholar
  8. 8.
    Aston-Jones G (2004) Locus coeruleus, A5 and A7 noradrenergic cell groups. In: Paxinos G (ed) The rat nervous system, vol 3rd edn. Elsevier, Amsterdam, pp 259–264Google Scholar
  9. 9.
    Aston-Jones G, Rajkowski J, Kubiak P, Valentino RJ, Shipley MT (1996) Role of the locus coeruleus in emotional activation. Prog Brain Res 107:379–402PubMedGoogle Scholar
  10. 10.
    Attems J, Thal DR, Jellinger KA (2012) The relationship between subcortical tau pathology and Alzheimer’s disease. Biochem Soc Trans 40:711–715. doi: 10.1042/BST20120034 PubMedGoogle Scholar
  11. 11.
    Berridge CW, Waterhouse BD (2003) The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Brain Res Rev 42:33–84PubMedGoogle Scholar
  12. 12.
    Bondareff W, Mountjoy CQ, Roth M (1982) Loss of neurons of origin of the adrenergic projection to cerebral cortex (nucleus locus ceruleus) in senile dementia. Neurology 32:164–168PubMedGoogle Scholar
  13. 13.
    Braak H, Del Tredici K (2011) Alzheimer’s pathogenesis: is there neuron-to-neuron propagation? Acta Neuropathol 121:589–595. doi: 10.1007/s00401-011-0825-z PubMedGoogle Scholar
  14. 14.
    Braak H, Del Tredici K (2011) The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol 121:171–181. doi: 10.1007/s00401-010-0789-4 PubMedGoogle Scholar
  15. 15.
    Braak H, Del Tredici K (2012) Where, when, and in what form does sporadic Alzheimer’s disease begin? Curr Opin Neurol 25:708–714. doi: 10.1097/WCO.0b013e32835a3432 PubMedGoogle Scholar
  16. 16.
    Brazeau P, Vale W, Burgus R, Ling N, Butcher M, Rivier J, Guillemin R (1973) Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science 179:77–79PubMedGoogle Scholar
  17. 17.
    Bremner JD, Krystal JH, Southwick SM, Charney DS (1996) Noradrenergic mechanisms in stress and anxiety: I. Preclinical studies. Synapse 23:28–38. doi: 10.1002/(SICI)1098-2396(199605)23:1<28:AID-SYN4>3.0.CO;2-J PubMedGoogle Scholar
  18. 18.
    Bremner JD, Krystal JH, Southwick SM, Charney DS (1996) Noradrenergic mechanisms in stress and anxiety: II. Clinical studies. Synapse 23:39–51. doi: 10.1002/(SICI)1098-2396(199605)23:1<39:AID-SYN5>3.0.CO;2-I PubMedGoogle Scholar
  19. 19.
    Burbach JP (2010) Neuropeptides from concept to online database Eur J Pharmacol 626:27–48. doi: 10.1016/j.ejphar.2009.10.015
  20. 20.
    Burgos-Ramos E, Hervas-Aguilar A, Aguado-Llera D, Puebla-Jimenez L, Hernandez-Pinto AM, Barrios V, Arilla-Ferreiro E (2008) Somatostatin and Alzheimer’s disease. Mol Cell Endocrinol 286:104–111. doi: 10.1016/j.mce.2008.01.014 PubMedGoogle Scholar
  21. 21.
    Carpentier V, Vaudry H, Laquerriere A, Tayot J, Leroux P (1996) Distribution of somatostatin receptors in the adult human brainstem. Brain Res 734:135–148PubMedGoogle Scholar
  22. 22.
    Chan-Palay V, Asan E (1989) Alterations in catecholamine neurons of the locus coeruleus in senile dementia of the Alzheimer type and in Parkinson’s disease with and without dementia and depression. J Comp Neurol 287:373–392. doi: 10.1002/cne.902870308 PubMedGoogle Scholar
  23. 23.
    Chessell IP, Black MD, Feniuk W, Humphrey PP (1996) Operational characteristics of somatostatin receptors mediating inhibitory actions on rat locus coeruleus neurones. Br J Pharmacol 117:1673–1678PubMedCentralPubMedGoogle Scholar
  24. 24.
    Craft S, Asthana S, Newcomer JW, Wilkinson CW, Matos IT, Baker LD, Cherrier M, Lofgreen C, Latendresse S, Petrova A, Plymate S, Raskind M, Grimwood K, Veith RC (1999) Enhancement of memory in Alzheimer disease with insulin and somatostatin, but not glucose. Arch Gen Psychiatry 56:1135–1140PubMedGoogle Scholar
  25. 25.
    Cross AJ, Crow TJ, Perry EK, Perry RH, Blessed G, Tomlinson BE (1981) Reduced dopamine-beta-hydroxylase activity in Alzheimer’s disease. Br Med J 282:93–94Google Scholar
  26. 26.
    Dahlström A, Fuxe K (1964) Evidence for the existence of monoamine neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brainstem neurons. Acta Physiol Scand 62:1–55Google Scholar
  27. 27.
    Davies P, Katzman R, Terry RD (1980) Reduced somatostatin-like immunoreactivity in cerebral cortex from cases of Alzheimer disease and Alzheimer senile dementa. Nature 288:279–280PubMedGoogle Scholar
  28. 28.
    De Martino C, Zamboni L (1967) Silver methenamine stain for electron microscopy. J Ultrastruct Res 19:273–282PubMedGoogle Scholar
  29. 29.
    Doraiswamy PM, Xiong GL (2006) Pharmacological strategies for the prevention of Alzheimer’s disease. Expert Opin Pharmacother 7:1–10. doi: 10.1517/14656566.7.1.S1 PubMedGoogle Scholar
  30. 30.
    Dournaud P, Delaere P, Hauw JJ, Epelbaum J (1995) Differential correlation between neurochemical deficits, neuropathology, and cognitive status in Alzheimer’s disease. Neurobiol Aging 16:817–823PubMedGoogle Scholar
  31. 31.
    Dutar P, Vaillend C, Viollet C, Billard JM, Potier B, Carlo AS, Ungerer A, Epelbaum J (2002) Spatial learning and synaptic hippocampal plasticity in type 2 somatostatin receptor knock-out mice. Neuroscience 112:455–466PubMedGoogle Scholar
  32. 32.
    Engin E, Stellbrink J, Treit D, Dickson CT (2008) Anxiolytic and antidepressant effects of intracerebroventricularly administered somatostatin: behavioral and neurophysiological evidence. Neuroscience 157:666–676. doi: 10.1016/j.neuroscience.2008.09.037 PubMedGoogle Scholar
  33. 33.
    Engin E, Treit D (2009) Anxiolytic and antidepressant actions of somatostatin: the role of sst2 and sst3 receptors. Psychopharmacology 206:281–289. doi: 10.1007/s00213-009-1605-5 PubMedGoogle Scholar
  34. 34.
    Epelbaum J et al (1986) Somatostatin in the central nervous system: physiology and pathological modifications. Prog Neurobiol 27:63–100. doi: 10.1016/0301-0082(86)90012-2
  35. 35.
    Epelbaum J, Bluet-Pajot MT, Llorens-Cortes C, Kordon C, Mounier F, Senut MC, Videau C (1990) 125I-[Tyr0, D-Trp8]somatostatin-14 binding sites in the locus coeruleus of the rat are located on both ascending and descending projecting noradrenergic cells. Peptides 11:21–27PubMedGoogle Scholar
  36. 36.
    Epelbaum J, Guillou JL, Gastambide F, Hoyer D, Duron E, Viollet C (2009) Somatostatin, Alzheimer’s disease and cognition: an old story coming of age? Prog Neurobiol 89:153–161. doi: 10.1016/j.pneurobio.2009.07.002 PubMedGoogle Scholar
  37. 37.
    Farris TW, Butcher LL, Oh JD, Woolf NJ (1995) Trophic-factor modulation of cortical acetylcholinesterase reappearance following transection of the medial cholinergic pathway in the adult rat. Exp Neurol 131:180–192PubMedGoogle Scholar
  38. 38.
    Ferriero DM, Sheldon RA, Messing RO (1994) Somatostatin enhances nerve growth factor-induced neurite outgrowth in PC12 cells. Brain Res Dev Brain Res 80:13–18PubMedGoogle Scholar
  39. 39.
    Foote SL, Bloom FE, Aston-Jones G (1983) Nucleus locus ceruleus: new evidence of anatomical and physiological specificity. Physiol Rev 63:844–914PubMedGoogle Scholar
  40. 40.
    Fuxe K, Hökfelt T, Ungerstedt U (1970) Central monoaminergic tracts. In: Clark WG, Del Guidice J (eds) Principles of Psychopharmacology, Academic Press, London, pp 87–96Google Scholar
  41. 41.
    Gagne C, Moyse E, Kocher L, Bour H, Pujol JF (1990) Light-microscopic localization of somatostatin binding sites in the locus coeruleus of the rat. Brain Res 530:196–204PubMedGoogle Scholar
  42. 42.
    Gahete MD, Rubio A, Duran-Prado M, Avila J, Luque RM, Castano JP (2010) Expression of somatostatin, cortistatin, and their receptors, as well as dopamine receptors, but not of neprilysin, are reduced in the temporal lobe of Alzheimer’s disease patients. J Alzheimers Dis 20:465–475. doi: 10.3233/JAD-2010-1385 PubMedGoogle Scholar
  43. 43.
    Gaspar P, Berger B, Febvret A, Vigny A, Henry JP (1989) Catecholamine innervation of the human cerebral cortex as revealed by comparative immunohistochemistry of tyrosine hydroxylase and dopamine-beta-hydroxylase. J Comp Neurol 279:249–271. doi: 10.1002/cne.902790208 PubMedGoogle Scholar
  44. 44.
    German DC, Manaye KF, White CL 3rd, Woodward DJ, McIntire DD, Smith WK, Kalaria RN, Mann DM (1992) Disease-specific patterns of locus coeruleus cell loss. Ann Neurol 32:667–676. doi: 10.1002/ana.410320510 PubMedGoogle Scholar
  45. 45.
    German DC, Nelson O, Liang F, Liang CL, Games D (2005) The PDAPP mouse model of Alzheimer’s disease: locus coeruleus neuronal shrinkage. J Comp Neurol 492:469–476. doi: 10.1002/cne.20744 PubMedGoogle Scholar
  46. 46.
    Greenberg MS, Tanev K, Marin MF, Pitman RK (2014) Stress, PTSD, and dementia. Alzheimers Dement 10:S155–S165. doi: 10.1016/j.jalz.2014.04.008 PubMedGoogle Scholar
  47. 47.
    Grzanna R, Fritschy JM (1991) Efferent projections of different subpopulations of central noradrenaline neurons. Prog Brain Res 88:89–101PubMedGoogle Scholar
  48. 48.
    Haglund M, Sjobeck M, Englund E (2006) Locus ceruleus degeneration is ubiquitous in Alzheimer’s disease: possible implications for diagnosis and treatment. Neuropathology 26:528–532PubMedGoogle Scholar
  49. 49.
    Hammerschmidt T, Kummer MP, Terwel D, Martinez A, Gorji A, Pape HC, Rommelfanger KS, Schroeder JP, Stoll M, Schultze J, Weinshenker D, Heneka MT (2013) Selective loss of noradrenaline exacerbates early cognitive dysfunction and synaptic deficits in APP/PS1 mice. Biol Psychiatry 73:454–463. doi: 10.1016/j.biopsych.2012.06.013 PubMedGoogle Scholar
  50. 50.
    Harro J, Oreland L, Vasar E, Bradwejn J (1995) Impaired exploratory behaviour after DSP-4 treatment in rats: implications for the increased anxiety after noradrenergic denervation. Eur Neuropsychopharmacol 5:447–455PubMedGoogle Scholar
  51. 51.
    Helyes Z, Pinter E, Sandor K, Elekes K, Banvolgyi A, Keszthelyi D, Szoke E, Toth DM, Sandor Z, Kereskai L, Pozsgai G, Allen JP, Emson PC, Markovics A, Szolcsanyi J (2009) Impaired defense mechanism against inflammation, hyperalgesia, and airway hyperreactivity in somatostatin 4 receptor gene-deleted mice. Proc Natl Acad Sci USA 106:13088–13093. doi: 10.1073/pnas.0900681106 PubMedCentralPubMedGoogle Scholar
  52. 52.
    Heneka MT, Nadrigny F, Regen T, Martinez-Hernandez A, Dumitrescu-Ozimek L, Terwel D, Jardanhazi-Kurutz D, Walter J, Kirchhoff F, Hanisch UK, Kummer MP (2010) Locus ceruleus controls Alzheimer’s disease pathology by modulating microglial functions through norepinephrine. Proc Natl Acad Sci USA 107:6058–6063. doi: 10.1073/pnas.0909586107 PubMedCentralPubMedGoogle Scholar
  53. 53.
    Horgan J, Miguel-Hidalgo JJ, Thrasher M, Bissette G (2007) Longitudinal brain corticotropin releasing factor and somatostatin in a transgenic mouse (TG2576) model of Alzheimer’s disease. J Alzheimers Dis 12:115–127PubMedCentralPubMedGoogle Scholar
  54. 54.
    Hoyer D, Bell GI, Berelowitz M, Epelbaum J, Feniuk W, Humphrey PP, O’Carroll AM, Patel YC, Schonbrunn A, Taylor JE et al (1995) Classification and nomenclature of somatostatin receptors. Trends Pharmacol Sci 16:86–88. doi: 10.1016/S0165-6147(00)88988-9
  55. 55.
    Inoue M, Nakajima S, Nakajima Y (1988) Somatostatin induces an inward rectification in rat locus coeruleus neurones through a pertussis toxin-sensitive mechanism. J Physiol 407:177–198PubMedCentralPubMedGoogle Scholar
  56. 56.
    Kampf C, Olsson I, Ryberg U, Sjostedt E, Ponten F (2012) Production of tissue microarrays, immunohistochemistry staining and digitalization within the human protein atlas. J Vis Exp JoVE. doi: 10.3791/3620
  57. 57.
    Kehr J, Yoshitake T (2006) Monitoring brain chemical signals by microdialysis. In: Grimes CA, Dickey EC, Pishko MV (eds) Encyclopedia of Sensors, vol 6. American Scientific Publishers, USA, pp 287–312Google Scholar
  58. 58.
    Kowall NW, Beal MF (1988) Cortical somatostatin, neuropeptide Y, and NADPH diaphorase neurons: normal anatomy and alterations in Alzheimer’s disease. Ann Neurol 23:105–114. doi: 10.1002/ana.410230202 PubMedGoogle Scholar
  59. 59.
    Krantic S, Robitaille Y, Quirion R (1992) Deficits in the somatostatin SS1 receptor sub-type in frontal and temporal cortices in Alzheimer’s disease. Brain Res 573:299–304PubMedGoogle Scholar
  60. 60.
    Kummer MP, Hammerschmidt T, Martinez A, Terwel D, Eichele G, Witten A, Figura S, Stoll M, Schwartz S, Pape HC, Schultze JL, Weinshenker D, Heneka MT (2014) Ear2 deletion causes early memory and learning deficits in APP/PS1 mice. J Neurosc 34:8845–8854. doi: 10.1523/JNEUROSCI.4027-13.2014 Google Scholar
  61. 61.
  62. 62.
    Le Maitre E, Barde SS, Palkovits M, Diaz-Heijtz R, Hokfelt TG (2013) Distinct features of neurotransmitter systems in the human brain with focus on the galanin system in locus coeruleus and dorsal raphe. Proc Natl Acad Sci USA 110:E536–E545. doi: 10.1073/pnas.1221378110 PubMedCentralPubMedGoogle Scholar
  63. 63.
    Levi-Montalcini R (1987) The nerve growth factor 35 years later. Science 237:1154–1162PubMedGoogle Scholar
  64. 64.
    Lin LC, Sibille E (2013) Reduced brain somatostatin in mood disorders: a common pathophysiological substrate and drug target? Front Pharmacol 4:110. doi: 10.3389/fphar.2013.00110 PubMedCentralPubMedGoogle Scholar
  65. 65.
    Mann DM, Lincoln J, Yates PO, Stamp JE, Toper S (1980) Changes in the monoamine containing neurones of the human CNS in senile dementia. Br J Psychiatry 136:533–541PubMedGoogle Scholar
  66. 66.
    Marino MD, Bourdelat-Parks BN, Cameron Liles L, Weinshenker D (2005) Genetic reduction of noradrenergic function alters social memory and reduces aggression in mice. Behav Brain Res 161:197–203. doi: 10.1016/j.bbr.2005.02.005 PubMedGoogle Scholar
  67. 67.
    Masaya Tohyama KT (1998) Atlas of neuroactive substances and their receptors in the rat. Oxford University Press, New YorkGoogle Scholar
  68. 68.
    Masuko S, Nakajima Y, Nakajima S, Yamaguchi K (1986) Noradrenergic neurons from the locus ceruleus in dissociated cell culture: culture methods, morphology, and electrophysiology. J Neurosci 6:3229–3241PubMedGoogle Scholar
  69. 69.
    McCarthy AD, Owens IJ, Bansal AT, McTighe SM, Bussey TJ, Saksida LM (2011) FK962 and donepezil act synergistically to improve cognition in rats: potential as an add-on therapy for Alzheimer’s disease. Pharmacol Biochem Behav 98:76–80. doi: 10.1016/j.pbb.2010.11.019 PubMedGoogle Scholar
  70. 70.
    McMillan PJ, White SS, Franklin A, Greenup JL, Leverenz JB, Raskind MA, Szot P (2011) Differential response of the central noradrenergic nervous system to the loss of locus coeruleus neurons in Parkinson’s disease and Alzheimer’s disease. Brain Res 1373:240–252. doi: 10.1016/j.brainres.2010.12.015 PubMedCentralPubMedGoogle Scholar
  71. 71.
    Melander T, Hökfelt T, Rokaeus A, Cuello AC, Oertel WH, Verhofstad A, Goldstein M (1986) Coexistence of galanin-like immunoreactivity with catecholamines, 5-hydroxytryptamine, GABA and neuropeptides in the rat CNS. J Neurosci 6:3640–3654PubMedGoogle Scholar
  72. 72.
    Moore RY, Bloom FE (1979) Central catecholamine neuron systems: anatomy and physiology of the norepinephrine and epinephrine systems. Annu Rev Neurosci 2:113–168. doi: 10.1146/ PubMedGoogle Scholar
  73. 73.
    Morilak DA, Barrera G, Echevarria DJ, Garcia AS, Hernandez A, Ma S, Petre CO (2005) Role of brain norepinephrine in the behavioral response to stress. Prog Neuropsychopharmacol Biol Psychiatry 29:1214–1224. doi: 10.1016/j.pnpbp.2005.08.007 PubMedGoogle Scholar
  74. 74.
    Morrison JH, Rogers J, Scherr S, Benoit R, Bloom FE (1985) Somatostatin immunoreactivity in neuritic plaques of Alzheimer’s patients. Nature 314:90–92PubMedGoogle Scholar
  75. 75.
    Murayama S, Saito Y (2004) Neuropathological diagnostic criteria for Alzheimer’s disease. Neuropathology 24:254–260PubMedGoogle Scholar
  76. 76.
    Nemeroff CB, Kizer JS, Reynolds GP, Bissette G (1989) Neuropeptides in Alzheimer’s disease: a postmortem study. Regul Pept 25:123–130PubMedGoogle Scholar
  77. 77.
    Nishimura A, Ueda S, Takeuchi Y, Matsushita H, Sawada T, Kawata M (1998) Vulnerability to aging in the rat serotonergic system. Acta Neuropathol 96:581–595PubMedGoogle Scholar
  78. 78.
    Norberg KA (1967) Transmitter histochemistry of the sympathetic adrenergic nervous system. Brain Res 5:125–170PubMedGoogle Scholar
  79. 79.
    Olpe HR, Steinmann MW, Pozza MF, Haas HL (1987) Comparative investigations on the actions of ACTH1-24, somatostatin, neurotensin, substance P and vasopressin on locus coeruleus neuronal activity in vitro. Naunyn Schmiedebergs Arch Pharmacol 336:434–437PubMedGoogle Scholar
  80. 80.
    Palkovits M, Epelbaum J, Tapia-Arancibia L, Kordon C (1982) Somatostatin in catecholamine-rich nuclei of the brainstem. Neuropeptides 3:139–144PubMedGoogle Scholar
  81. 81.
    Palmer AM, Wilcock GK, Esiri MM, Francis PT, Bowen DM (1987) Monoaminergic innervation of the frontal and temporal lobes in Alzheimer’s disease. Brain Res 401:231–238PubMedGoogle Scholar
  82. 82.
    Paxinos G, Huang XF (1995) Atlas of the human brainstem. Academic Press Inc., San DiegoGoogle Scholar
  83. 83.
    Peng I, Binder LI, Black MM (1986) Biochemical and immunological analyses of cytoskeletal domains of neurons. J Cell Biol 102:252–262PubMedGoogle Scholar
  84. 84.
    Ramos B, Baglietto-Vargas D, del Rio JC, Moreno-Gonzalez I, Santa-Maria C, Jimenez S, Caballero C, Lopez-Tellez JF, Khan ZU, Ruano D, Gutierrez A, Vitorica J (2006) Early neuropathology of somatostatin/NPY GABAergic cells in the hippocampus of a PS1xAPP transgenic model of Alzheimer’s disease. Neurobiol Aging 27:1658–1672. doi: 10.1016/j.neurobiolaging.2005.09.022 PubMedGoogle Scholar
  85. 85.
    Robertson IH (2013) A noradrenergic theory of cognitive reserve: implications for Alzheimer’s disease. Neurobiol Aging 34:298–308. doi: 10.1016/j.neurobiolaging.2012.05.019 PubMedGoogle Scholar
  86. 86.
    Rommelfanger KS, Edwards GL, Freeman KG, Liles LC, Miller GW, Weinshenker D (2007) Norepinephrine loss produces more profound motor deficits than MPTP treatment in mice. Proc Natl Acad Sci USA 104:13804–13809. doi: 10.1073/pnas.0702753104 PubMedCentralPubMedGoogle Scholar
  87. 87.
    Ronnback A, Sagelius H, Bergstedt KD, Naslund J, Westermark GT, Winblad B, Graff C (2012) Amyloid neuropathology in the single Arctic APP transgenic model affects interconnected brain regions. Neurobiol Aging 33(831):e811–e839. doi: 10.1016/j.neurobiolaging.2011.07.012 Google Scholar
  88. 88.
    Ronnback A, Zhu S, Dillner K, Aoki M, Lilius L, Naslund J, Winblad B, Graff C (2011) Progressive neuropathology and cognitive decline in a single Arctic APP transgenic mouse model. Neurobiol Aging 32:280–292. doi: 10.1016/j.neurobiolaging.2009.02.021 PubMedGoogle Scholar
  89. 89.
    Rossor MN, Emson PC, Mountjoy CQ, Roth M, Iversen LL (1980) Reduced amounts of immunoreactive somatostatin in the temporal cortex in senile dementia of Alzheimer type. Neurosci Lett 20:373–377PubMedGoogle Scholar
  90. 90.
    Saito T, Iwata N, Tsubuki S, Takaki Y, Takano J, Huang SM, Suemoto T, Higuchi M, Saido TC (2005) Somatostatin regulates brain amyloid beta peptide Abeta42 through modulation of proteolytic degradation. Nat Med 11:434–439. doi: 10.1038/nm1206 PubMedGoogle Scholar
  91. 91.
    Savonenko A, Xu GM, Melnikova T, Morton JL, Gonzales V, Wong MP, Price DL, Tang F, Markowska AL, Borchelt DR (2005) Episodic-like memory deficits in the APPswe/PS1dE9 mouse model of Alzheimer’s disease: relationships to beta-amyloid deposition and neurotransmitter abnormalities. Neurobiol Dis 18:602–617. doi: 10.1016/j.nbd.2004.10.022 PubMedGoogle Scholar
  92. 92.
    Schalling M, Seroogy K, Hökfelt T, Chai SY, Hallman H, Persson H, Larhammar D, Ericsson A, Terenius L, Graffi J et al (1988) Neuropeptide tyrosine in the rat adrenal gland–immunohistochemical and in situ hybridization studies. Neuroscience 24:337–349PubMedGoogle Scholar
  93. 93.
    Schatzberg F, Schildkraut JJ (1995) Recent studies on norepinephrine systems in mood disorders. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology. Raven Press, New York, pp 911–920Google Scholar
  94. 94.
    Sepehry AA, Lee PE, Hsiung GY, Beattie BL, Jacova C (2012) Effect of selective serotonin reuptake inhibitors in Alzheimer’s disease with comorbid depression: a meta-analysis of depression and cognitive outcomes. Drugs Aging 29:793–806. doi: 10.1007/s40266-012-0012-5 PubMedGoogle Scholar
  95. 95.
    Shi TJ, Xiang Q, Zhang MD, Barde S, Kai-Larsen Y, Fried K, Josephson A, Gluck L, Deyev SM, Zvyagin AV, Schulz S, Hokfelt T (2014) Somatostatin and its 2A receptor in dorsal root ganglia and dorsal horn of mouse and human: expression, trafficking and possible role in pain. Mol Pain 10:12. doi: 10.1186/1744-8069-10-12 PubMedCentralPubMedGoogle Scholar
  96. 96.
    Stengel A, Rivier J, Tache Y (2013) Modulation of the adaptive response to stress by brain activation of selective somatostatin receptor subtypes. Peptides 42:70–77. doi: 10.1016/j.peptides.2012.12.022 PubMedCentralPubMedGoogle Scholar
  97. 97.
    Szabadi E (2013) Functional neuroanatomy of the central noradrenergic system. J Psychopharmacol 27:659–693. doi: 10.1177/0269881113490326 PubMedGoogle Scholar
  98. 98.
    Szot P (2012) Common factors among Alzheimer’s disease, Parkinson’s disease, and epilepsy: possible role of the noradrenergic nervous system. Epilepsia 53(Suppl 1):61–66. doi: 10.1111/j.1528-1167.2012.03476.x PubMedGoogle Scholar
  99. 99.
    Szot P, White SS, Greenup JL, Leverenz JB, Peskind ER, Raskind MA (2006) Compensatory changes in the noradrenergic nervous system in the locus ceruleus and hippocampus of postmortem subjects with Alzheimer’s disease and dementia with Lewy bodies. J Neurosc 26:467–478. doi: 10.1523/JNEUROSCI.4265-05.2006 Google Scholar
  100. 100.
    Tatemoto K, Rokaeus A, Jornvall H, McDonald TJ, Mutt V (1983) Galanin—a novel biologically active peptide from porcine intestine. FEBS Lett 164:124–128. doi: 10.1016/0014-5793(83)80033-7
  101. 101.
    Thoss VS, Perez J, Duc D, Hoyer D (1995) Embryonic and postnatal mRNA distribution of five somatostatin receptor subtypes in the rat brain. Neuropharmacology 34:1673–1688PubMedGoogle Scholar
  102. 102.
    Tokita K, Inoue T, Yamazaki S, Wang F, Yamaji T, Matsuoka N, Mutoh S (2005) FK962, a novel enhancer of somatostatin release, exerts cognitive-enhancing actions in rats. Eur J Pharmacol 527:111–120. doi: 10.1016/j.ejphar.2005.10.022 PubMedGoogle Scholar
  103. 103.
    Tomlinson BE, Irving D, Blessed G (1981) Cell loss in the locus coeruleus in senile dementia of Alzheimer type. J Neurol Sci 49:419–428PubMedGoogle Scholar
  104. 104.
    Toppila J, Niittymaki P, Porkka-Heiskanen T, Stenberg D (2000) Intracerebroventricular and locus coeruleus microinjections of somatostatin antagonist decrease REM sleep in rats. Pharmacol Biochem Behav 66:721–727PubMedGoogle Scholar
  105. 105.
    Toth K, Eross L, Vajda J, Halasz P, Freund TF, Magloczky Z (2010) Loss and reorganization of calretinin-containing interneurons in the epileptic human hippocampus. Brain 133:2763–2777. doi: 10.1093/brain/awq149 PubMedCentralPubMedGoogle Scholar
  106. 106.
    Ueda S, Aikawa M, Ishizuya-Oka A, Yamaoka S, Koibuchi N, Yoshimoto K (2000) Age-related dopamine deficiency in the mesostriatal dopamine system of zitter mutant rats: regional fiber vulnerability in the striatum and the olfactory tubercle. Neuroscience 95:389–398PubMedGoogle Scholar
  107. 107.
    Vale W, Brazeau P, Rivier C, Brown M, Boss B, Rivier J, Burgus R, Ling N, Guillemin R (1975) Somatostatin. Recent Prog Horm Res 31:365–397PubMedGoogle Scholar
  108. 108.
    van de Nes JA, Konermann S, Nafe R, Swaab DF (2006) Beta-protein/A4 deposits are not associated with hyperphosphorylated tau in somatostatin neurons in the hypothalamus of Alzheimer’s disease patients. Acta Neuropathol 111:126–138. doi: 10.1007/s00401-005-0018-8 PubMedGoogle Scholar
  109. 109.
    van Luijtelaar MG, Steinbusch HW, Tonnaer JA (1988) Aberrant morphology of serotonergic fibers in the forebrain of the aged rat. Neurosci Lett 95:93–96PubMedGoogle Scholar
  110. 110.
    van Luijtelaar MG, Tonnaer JA, Steinbusch HW (1992) Aging of the serotonergic system in the rat forebrain: an immunocytochemical and neurochemical study. Neurobiol Aging 13:201–215PubMedGoogle Scholar
  111. 111.
    Vepsalainen S, Helisalmi S, Koivisto AM, Tapaninen T, Hiltunen M, Soininen H (2007) Somatostatin genetic variants modify the risk for Alzheimer’s disease among Finnish patients. J Neurol 254:1504–1508. doi: 10.1007/s00415-007-0539-2 PubMedGoogle Scholar
  112. 112.
    Viollet C, Lepousez G, Loudes C, Videau C, Simon A, Epelbaum J (2008) Somatostatinergic systems in brain: networks and functions. Mol Cell Endocrinol 286:75–87. doi: 10.1016/j.mce.2007.09.007 PubMedGoogle Scholar
  113. 113.
    Viollet C, Vaillend C, Videau C, Bluet-Pajot MT, Ungerer A, L’Heritier A, Kopp C, Potier B, Billard J, Schaeffer J, Smith RG, Rohrer SP, Wilkinson H, Zheng H, Epelbaum J (2000) Involvement of sst2 somatostatin receptor in locomotor, exploratory activity and emotional reactivity in mice. Eur J Neurosci 12:3761–3770PubMedGoogle Scholar
  114. 114.
    Watabe Y, Yoshimoto K, Eguchi M, Ueda S (2005) Degeneration of monoaminergic fibers in the aged micrencephalic rat. Neurosci Lett 385:82–86. doi: 10.1016/j.neulet.2005.05.020 PubMedGoogle Scholar
  115. 115.
    Weinshenker D (2008) Functional consequences of locus coeruleus degeneration in Alzheimer’s disease. Curr Alzheimer Res 5:342–345PubMedGoogle Scholar
  116. 116.
    Xu ZQ, Shi TJ, Hökfelt T (1998) Galanin/GMAP- and NPY-like immunoreactivities in locus coeruleus and noradrenergic nerve terminals in the hippocampal formation and cortex with notes on the galanin-R1 and -R2 receptors. J Comp Neurol 392:227–251PubMedGoogle Scholar
  117. 117.
    Xue S, Jia L, Jia J (2009) Association between somatostatin gene polymorphisms and sporadic Alzheimer’s disease in Chinese population. Neurosci Lett 465:181–183. doi: 10.1016/j.neulet.2009.09.002 PubMedGoogle Scholar
  118. 118.
    Yeung M, Treit D (2012) The anxiolytic effects of somatostatin following intra-septal and intra-amygdalar microinfusions are reversed by the selective sst2 antagonist PRL2903. Pharmacol Biochem Behav 101:88–92. doi: 10.1016/j.pbb.2011.12.012 PubMedGoogle Scholar
  119. 119.
    Zarow C, Lyness SA, Mortimer JA, Chui HC (2003) Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. Arch Neurol 60:337–341PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Csaba Ádori
    • 1
    Email author
  • Laura Glück
    • 2
  • Swapnali Barde
    • 1
  • Takashi Yoshitake
    • 3
  • Gabor G. Kovacs
    • 4
  • Jan Mulder
    • 1
    • 5
  • Zsófia Maglóczky
    • 6
  • László Havas
    • 7
  • Kata Bölcskei
    • 8
  • Nicholas Mitsios
    • 1
    • 5
  • Mathias Uhlén
    • 9
  • János Szolcsányi
    • 8
  • Jan Kehr
    • 3
  • Annica Rönnbäck
    • 10
  • Thue Schwartz
    • 11
  • Jens F. Rehfeld
    • 12
  • Tibor Harkany
    • 13
    • 14
  • Miklós Palkovits
    • 15
    • 16
  • Stefan Schulz
    • 2
  • Tomas Hökfelt
    • 1
    Email author
  1. 1.Department of Neuroscience, Retzius LaboratoryKarolinska InstitutetStockholmSweden
  2. 2.Institute of Pharmacology and ToxicologyJena University Hospital, Friedrich-Schiller UniversityJenaGermany
  3. 3.Department of Physiology and PharmacologyKarolinska InstitutetStockholmSweden
  4. 4.Institute of NeurologyMedical University of ViennaViennaAustria
  5. 5.Science for Life LaboratoryKarolinska InstitutetStockholmSweden
  6. 6.Laboratory of Cerebral Cortex ResearchInstitute of Experimental Medicine of the Hungarian Academy of SciencesBudapestHungary
  7. 7.Department of PathologySzent Borbála HospitalTatabányaHungary
  8. 8.Department of Pharmacology and PharmacotherapyUniversity of Pécs Medical SchoolPécsHungary
  9. 9.Science for Life LaboratoryRoyal Institute of TechnologyStockholmSweden
  10. 10.Department of Neurobiology, Care Sciences and SocietyKarolinska Institutet Alzheimer Disease Research Center (KI-ADRC), Karolinska InstitutetStockholmSweden
  11. 11.Section for Metabolic Receptology and Enteroendocrinology, Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Novo Nordisk Foundation Center for Basic Metabolic ResearchUniversity of CopenhagenCopenhagenDenmark
  12. 12.Department of Clinical Biochemistry, RigshospitaletUniversity of CopenhagenCopenhagenDenmark
  13. 13.Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSweden
  14. 14.Department of Molecular Neurosciences, Center for Brain ResearchMedical University of ViennaViennaAustria
  15. 15.Neuromorphological and Neuroendocrine Research Laboratory, Department of Anatomy, Histology and EmbryologySemmelweis University and the Hungarian Academy of SciencesBudapestHungary
  16. 16.Human Brain Tissue Bank and LaboratorySemmelweis UniversityBudapestHungary

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