Molecular Neurobiology

, Volume 41, Issue 2–3, pp 129–137 | Cite as

Cyclic GMP and Nitric Oxide Synthase in Aging and Alzheimer's Disease

  • Katarzyna Urszula Domek-ŁopacińskaEmail author
  • Joanna B. Strosznajder


Cyclic guanosine monophosphate (cGMP) is an important secondary messenger synthesized by the guanylyl cyclases which are found in the soluble (sGC) and particular isoforms. In the central nervous system, the nitric oxide (NO)-sensitive sGC isoform is the major enzyme responsible for cGMP synthesis. Phosphodiesterases (PDEs) are enzymes for hydrolysis of cGMP in the brain, and they are mainly isoforms 2, 5, and 9. The NO/cGMP signaling pathway has been shown to play an important role in the process underlying learning and memory. Aging is associated with an increase in PDE expression and activity and a decrease in cGMP concentration. In addition, aging is also associated with an enhancement of neuronal NO synthase, a lowering of endothelial, and no alteration in inducible activity. The observed changes in NMDA receptor density along with the Ca2+/NO/cGMP pathway underscore the lower synaptic plasticity and cognitive performance during aging. This notion is in agreement with last data indicating that inhibitors of PDE2 and PDE9 improve learning and memory in older rats. In this review, we focus on recent studies supporting the role of Ca2+/NO/cGMP pathway in aging and Alzheimer's disease.


Aging Alzheimer's disease Brain Cyclic GMP Memory Nitric oxide Phosphodiesterases 



Alzheimer's disease


Central nervous system


Cyclic GMP




cGMP-Dependent protein kinase G


Guanylyl cyclase (soluble isoform)


NO synthase


  1. 1.
    Abe T, Tohgi H, Murata T, Isobe C, Sato C (2001) Reduction in asymmetrical dimethylarginine, an endogenous nitric oxide synthase inhibitor, in the cerebrospinal fluid during ageing and in patients with Alzheimer's disease. Neurosci Lett 312:177–179CrossRefPubMedGoogle Scholar
  2. 2.
    Atochin DN, Wang A, Liu VW, Critchlow JD, Dantas AP, Looft-Wilson R, Murata T, Salomone S, Shin HK, Ayata C, Moskowitz MA, Michel T, Sessa WC, Huang PL (2007) The phosphorylation state of eNOS modulates vascular reactivity and outcome of cerebral ischemia in vivo. J Clin Invest 117(7):961–967CrossRefGoogle Scholar
  3. 3.
    Baltrons MA, Pifarré P, Ferrer I, Carot JM, García A (2004) Reduced expression of NO-sensitive guanylyl cyclase in reactive astrocytes of Alzheimer disease, Creutzfeldt-Jakob disease, and multiple sclerosis brains. Neurobiol Dis 17(3):462–472CrossRefPubMedGoogle Scholar
  4. 4.
    Barger SW, Fiscus RR, Ruth P, Hofmann F, Mattson MP (1995) Role of cyclic GMP in the regulation of neuronal calcium and survival by secreted forms of beta-A-beta precursor. J Neurochem 64:2087–2096PubMedCrossRefGoogle Scholar
  5. 5.
    Bender AT, Beavo JA (2006) Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev 58(3):488–520CrossRefPubMedGoogle Scholar
  6. 6.
    Bobba A, Atlante A, Moro L, Calissano P, Marra E (2007) Nitric oxide has dual opposite roles during early and late phases of apoptosis in cerebellar granule neurons. Apoptosis 12(9):1597–1610CrossRefPubMedGoogle Scholar
  7. 7.
    Bonkale WL, Winblad B, Ravid R, Cowburn RF (1995) Reduced nitric oxide responsive soluble guanylyl cyclase activity in the superior temporal cortex of patients with Alzheimer's disease. Neurosci Lett 187:5–8CrossRefPubMedGoogle Scholar
  8. 8.
    Caretti A, Bianciardi P, Ronchi R, Fantacci M, Guazzi M, Samaja M (2008) Phosphodiesterase-5 inhibition abolishes neuron apoptosis induced by chronic hypoxia independently of hypoxia-inducible factor-1alpha signaling. Exp Biol Med (Maywood) 233(10):1222–1230CrossRefGoogle Scholar
  9. 9.
    Chalimoniuk M, Stolecka A, Cakała M, Hauptmann S, Schulz K, Lipka U, Leuner K, Eckert A, Muller WE, Strosznajder JB (2007) A-beta enhances cytosolic phospholipase A2 level and arachidonic acid release via nitric oxide in APP-transfected PC12 cells. Acta Biochim Pol 54(3):611–623PubMedGoogle Scholar
  10. 10.
    Chalimoniuk M, Strosznajder JB (1998) Ageing modulates nitric oxide synthesis and cGMP levels in hippocampus and cerebellum. Effects of A-beta beta peptide. Mol Chem Neuropathol 35:77–95CrossRefPubMedGoogle Scholar
  11. 11.
    Cho DH, Nakamura T, Fang J, Cieplak P, Godzik A, Gu Z, Lipton SA (2009) S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science 324(5923):102–105CrossRefPubMedGoogle Scholar
  12. 12.
    Chrissobolis S, Faraci FM (2008) The role of oxidative stress and NADPH oxidase in cerebrovascular disease. Trends Mol Med 14(11):495–502CrossRefPubMedGoogle Scholar
  13. 13.
    Ciani E, Guidi S, Bartesaghi R, Contestabile A (2002) Nitric oxide regulates cGMP-dependent cAMP-responsive element binding protein phosphorylation and Bcl-2 expression in cerebellar neurons: implication for a survival role of nitric oxide. J Neurochem 82:1282–1289CrossRefPubMedGoogle Scholar
  14. 14.
    Colton CA, Brown CM, Czapiga M, Vitek MP (2002) Apolipoprotein-E allele-specific regulation of nitric oxide production. Ann N Y Acad Sci 962:212–225CrossRefPubMedGoogle Scholar
  15. 15.
    Combs CK, Karlo JC, Kao SC, Landreth GE (2001) A-beta stimulation of microglia and monocytes results in TNFalpha-dependent expression of inducible nitric oxide synthase and neuronal apoptosis. J Neurosci 21:1179–1188PubMedGoogle Scholar
  16. 16.
    Connelly L, Madhani M, Hobbs AJ (2005) Resistance to endotoxic shock in endothelial nitric-oxide synthase (eNOS) knock-out mice: a pro-inflammatory role for eNOS-derived NO in vivo. J Biol Chem 280(11):10040–10046CrossRefPubMedGoogle Scholar
  17. 17.
    Czapski GA, Cakala M, Chalimoniuk M, Gajkowska B, Strosznajder JB (2007) Role of nitric oxide in the brain during lipopolysaccharide-evoked systemic inflammation. J Neurosci Res 85(8):1694–1703CrossRefPubMedGoogle Scholar
  18. 18.
    Danysz W, Zajaczkowski W, Parsons CG (1995) Modulation of learning processes by ionotropic glutamate receptor ligands. Behav Pharmacol 6(5 And 6):455–474PubMedGoogle Scholar
  19. 19.
    Domek-Łopacińska K, Markerink-van Ittersum M, Steinbusch H, de Vente J (2005) Changes in expression of cGMP selective phosphodiesterases 2, 5 and 9 in the rat brain during ageing. BMC Pharmacology 5(Suppl 1):15CrossRefGoogle Scholar
  20. 20.
    Domek-Łopacińska K, Strosznajder JB (2005) Cyclic GMP metabolism and its role in brain physiology. J Physiol Pharmacol 56(Supplement 2):15–34PubMedGoogle Scholar
  21. 21.
    Domek-Łopacińska K, Strosznajder JB (2008) The effect of selective inhibition of cyclic GMP hydrolyzing phosphodiesterases 2 and 5 on learning and memory processes and nitric oxide synthase activity in brain during ageing. Brain Res 1216:68–77CrossRefPubMedGoogle Scholar
  22. 22.
    Domek-Łopacińska K, van de Waarenburg M, Markerink-van IM, Steinbusch HW, de Vente J (2005) Nitric oxide-induced cGMP synthesis in the cholinergic system during the development and ageing of the rat brain. Brain Res Dev Brain Res 158(1–2):72–81PubMedGoogle Scholar
  23. 23.
    Faraci FM (2006) Protecting the brain with eNOS: run for your life. Circulation Res 99(10):1029–1030CrossRefPubMedGoogle Scholar
  24. 24.
    Fiscus RR (2002) Involvement of cyclic GMP and protein kinase G in the regulation of apoptosis and survival in neural cells. Neurosignals 11:175–190CrossRefPubMedGoogle Scholar
  25. 25.
    Garthwaite J (1991) Glutamate, nitric oxide and cell–cell signalling in the nervous system. Trends Neurosci 14:60–67CrossRefPubMedGoogle Scholar
  26. 26.
    Garthwaite J (2008) Concepts of neural nitric oxide-mediated transmission. Eur J Neurosci 27:2783–2802CrossRefPubMedGoogle Scholar
  27. 27.
    Ha KS, Kim KM, Kwon YG, Bai SK, Nam WD, Yoo YM, Kim PK, Chung HT, Billiar TR, Kim YM (2003) Nitric oxide prevents 6 hydroxydopamine-induced apoptosis in PC12 cells through cGMP-dependent PI3 kinase/Akt activation. FASEB J 17:1036–1047CrossRefPubMedGoogle Scholar
  28. 28.
    Hilbig H, Holler J, Dinse HR, Bidmon HJ (2002) In contrast to neuronal NOS-I, the inducible NOS-II expression in ageing brains is modified by enriched environmental conditions. Exp Toxicol Pathol 53:427–431CrossRefPubMedGoogle Scholar
  29. 29.
    Ibarra C, Nedvetsky PI, Gerlach M, Riederer P, Schmidt HH (2001) Regional and age-dependent expression of the nitric oxide receptor, soluble guanylyl cyclase, in the human brain. Brain Res 907:54–60CrossRefPubMedGoogle Scholar
  30. 30.
    Jęśko H, Chalimoniuk M, Strosznajder JB (2003) Activation of constitutive nitric oxide synthase(s) and absence of inducible isoform in aged rat brain. Neurochem Int 42:315–322CrossRefPubMedGoogle Scholar
  31. 31.
    Keil U, Bonert A, Marques CA, Scherping I, Weyermann J, Strosznajder JB, Müller-Spahn F, Haass C, Czech C, Pradier L, Müller WE, Eckert A (2004) A-beta-induced changes in nitric oxide production and mitochondrial activity lead to apoptosis. J Biol Chem 279(48):50310–50320CrossRefPubMedGoogle Scholar
  32. 32.
    La Porta CA, Comolli R (1999) Age-dependent modulation of PKC isoforms and NOS activity and expression in rat cortex, striatum, and hippocampus. Exp Gerontol 34(7):863–874CrossRefPubMedGoogle Scholar
  33. 33.
    Law A, O'Donnell J, Gauthier S, Quirion R (2002) Neuronal and inducible nitric oxide synthase expressions and activities in the hippocampi and cortices of young adult, aged cognitively unimpaired, and impaired Long-Evans rats. Neuroscience 112:267–275CrossRefPubMedGoogle Scholar
  34. 34.
    Liu P, Smith PF, Appleton I, Darlington CL, Bilkey DK (2003) Regional variations and age-related changes in nitric oxide synthase and arginase in the sub-regions of the hippocampus. Neuroscience 119(3):679–687CrossRefPubMedGoogle Scholar
  35. 35.
    Liu P, Smith PF, Appleton I, Darlington CL, Bilkey DK (2004) Age-related changes in nitric oxide synthase and arginase in the rat prefrontal cortex. Neurobiol Aging 25(4):547–552CrossRefPubMedGoogle Scholar
  36. 36.
    Liu P, Smith PF, Appleton I, Darlington CL, Bilkey DK (2005) Hippocampal nitric oxide synthase and arginase and age-associated behavioral deficits. Hippocampus 15(5):642–655CrossRefPubMedGoogle Scholar
  37. 37.
    Llansola M, Hernandez-Viadel M, Erceg S, Montoliu C, Felipo V (2009) Increasing the function of the glutamate–nitric oxide–cyclic guanosine monophosphate pathway increases the ability to learn a Y-maze task. J Neurosci Res 87(10):2351–2355CrossRefPubMedGoogle Scholar
  38. 38.
    Luth HJ, Munch G, Arendt T (2002) Aberrant expression of NOS isoforms in Alzheimer's disease is structurally related to nitrotyrosine formation. Brain Res 953:135–143CrossRefPubMedGoogle Scholar
  39. 39.
    Mattson MP, Guo ZH, Geiger JD (1999) Secreted form of A-beta precursor protein enhances basal glucose and glutamate transport and protects against oxidative impairment of glucose and glutamate transport in synaptosomes by a cyclic GMP-mediated mechanism. J Neurochem 73:532–537CrossRefPubMedGoogle Scholar
  40. 40.
    Mayhan WG, Arrick DM, Sharpe GM, Sun H (2008) Age-related alterations in reactivity of cerebral arterioles: role of oxidative stress. Microcirculation 15(3):225–236CrossRefPubMedGoogle Scholar
  41. 41.
    McCann SM (1997) The nitric oxide hypothesis of aging. Exp Gerontol 32(4–5):431–440CrossRefPubMedGoogle Scholar
  42. 42.
    Meyer RC, Spangler EL, Kametani H, Ingram DK (1998) Age-associated memory impairment. Assessing the role of nitric oxide. Ann N Y Acad Sci 854:307–317CrossRefPubMedGoogle Scholar
  43. 43.
    Mollace V, Rodino P, Massoud R, Rotiroti D, Nistico G (1995) Age-dependent changes of NO synthase activity in the rat brain. Biochem Biophys Res Commun 215:822–827CrossRefPubMedGoogle Scholar
  44. 44.
    Nakamura T, Lipton SA (2009) Cell death: protein misfolding and neurodegenerative diseases. Apoptosis 14(4):455–468CrossRefPubMedGoogle Scholar
  45. 45.
    Paris D, Town T, Parker TA, Tan J, Humphrey J, Crawford F, Mullan M (1999) Inhibition of Alzheimer's beta-A-beta induced vasoactivity and proinflammatory response in microglia by a cGMP-dependent mechanism. Exp Neurol 157:211–221CrossRefPubMedGoogle Scholar
  46. 46.
    Paul V, Reddy L, Ekambaram P (2005) A reversal by l-arginine and sodium nitroprusside of ageing-induced memory impairment in rats by increasing nitric oxide concentration in the hippocampus. Indian J Physiol Pharmacol 49(2):179–186PubMedGoogle Scholar
  47. 47.
    Piedrafita B, Cauli O, Montoliu C, Felipo V (2007) The function of the glutamate–nitric oxide–cGMP pathway in brain in vivo and learning ability decrease in parallel in mature compared with young rats. Learn Mem 14(4):254–2588CrossRefPubMedGoogle Scholar
  48. 48.
    Puzzo D, Vitolo O, Trinchese F, Jacob JP, Palmeri A, Arancio O (2005) Amyloid-beta peptide inhibits activation of the nitric oxide/cGMP/cAMP-responsive element-binding protein pathway during hippocampal synaptic plasticity. J Neurosci 25(29):6887–6897CrossRefPubMedGoogle Scholar
  49. 49.
    Puzzo D, Staniszewski A, Deng SX, Privitera L, Leznik E, Liu S, Zhang H, Feng Y, Palmeri A, Landry DW, Arancio O (2009) Phosphodiesterase 5 inhibition improves synaptic function, memory, and amyloid-beta load in an Alzheimer's disease mouse model. J Neurosci 29(25):8075–8086CrossRefPubMedGoogle Scholar
  50. 50.
    Quinn J, Davis F, Woodward WR, Eckenstein F (2001) Beta-A-beta plaques induce neuritic dystrophy of nitric oxide-producing neurons in a transgenic mouse model of Alzheimer's disease. Exp Neurol 168:203–212CrossRefPubMedGoogle Scholar
  51. 51.
    Reyes-Irisarri E, Markerink-Van IM, Mengod G, de Vente J (2007) Expression of the cGMP-specific phosphodiesterases 2 and 9 in normal and Alzheimer's disease human brains. Eur J Neurosci 25(11):3332–3338CrossRefPubMedGoogle Scholar
  52. 52.
    Reneerkens OA, Rutten K, Steinbusch HW, Blokland A, Prickaerts J (2009) Selective phosphodiesterase inhibitors: a promising target for cognition enhancement. Psychopharmacology (Berl) 202(1–3):419–443CrossRefGoogle Scholar
  53. 53.
    Rutten K, Prickaerts J, Hendrix M, van der Staay FJ, Sik A, Blokland A (2007) Time-dependent involvement of cAMP and cGMP in consolidation of object memory: studies using selective phosphodiesterase type 2, 4 and 5 inhibitors. Eur J Pharmacol 558(1–3):107–112CrossRefPubMedGoogle Scholar
  54. 54.
    Rutten K, Prickaerts J, Schaenzle G, Rosenbrock H, Blokland A (2008) Sub-chronic rolipram treatment leads to a persistent improvement in long-term object memory in rats. Neurobiol Learn Mem 90(3):569–575CrossRefPubMedGoogle Scholar
  55. 55.
    Siuciak JA, McCarthy SA, Chapin DS, Martin AN, Harms JF, Schmidt CJ (2008) Behavioral characterization of mice deficient in the phosphodiesterase-10A (PDE10A) enzyme on a C57/Bl6N congenic background. Neuropharmacology 54(2):417–427CrossRefPubMedGoogle Scholar
  56. 56.
    Siuciak JA, McCarthy SA, Chapin DS, Martin AN (2008) Behavioral and neurochemical characterization of mice deficient in the phosphodiesterase-4B (PDE4B) enzyme. Psychopharmacology (Berl) 197(1):115–126CrossRefGoogle Scholar
  57. 57.
    Strosznajder JB, Jeśko H, Zambrzycka A, Eckert A, Chalimoniuk M (2004) Age-related alteration of activity and gene expression of endothelial nitric oxide synthase in different parts of the brain in rats. Neurosci Lett 370(2–3):175–179CrossRefPubMedGoogle Scholar
  58. 58.
    Vallebuona F, Raiteri M (1995) Age-related changes in the NMDA receptor/nitric oxide/cGMP pathway in the hippocampus and cerebellum of freely moving rats subjected to transcerebral microdialysis. Eur J Neurosci 7:694–701CrossRefPubMedGoogle Scholar
  59. 59.
    van der Staay FJ, Rutten K, Bärfacker L, Devry J, Erb C, Heckroth H, Karthaus D, Tersteegen A, van Kampen M, Blokland A, Prickaerts J, Reymann KG, Schröder UH, Hendrix M (2008) The novel selective PDE9 inhibitor BAY 73-6691 improves learning and memory in rodents. Neuropharmacology 55(5):908–918CrossRefPubMedGoogle Scholar
  60. 60.
    Wirtz-Brugger F, Giovanni A (2000) Guanosine 3′,5′-cyclic monophosphate mediated inhibition of cell death induced by nerve growth factor withdrawal and beta-A-beta: protective effects of propentofylline. Neuroscience 99:737–750CrossRefPubMedGoogle Scholar
  61. 61.
    Yew DT, Wong HW, Li WP, Lai HW, Yu WH (1999) Nitric oxide synthase neurons in different areas of normal aged and Alzheimer's brains. Neuroscience 89:675–689CrossRefPubMedGoogle Scholar
  62. 62.
    Yu W, Juang S, Lee J, Liu T, Cheng J (2000) Decrease of neuronal nitric oxide synthase in the cerebellum of aged rats. Neurosci Lett 291(1):37–40CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Katarzyna Urszula Domek-Łopacińska
    • 1
    Email author
  • Joanna B. Strosznajder
    • 1
  1. 1.Department of Cellular Signaling, M. Mossakowski Medical Research CenterPolish Academy of SciencesWarsawPoland

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