Neuronal nitric oxide synthase: Structure, subcellular localization, regulation, and clinical implications

Nitric Oxide - Tập 20 - Trang 223-230 - 2009
Li Zhou1, Dong-Ya Zhu1
1Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing 210029, China

Tài liệu tham khảo

Kang, 2004, Regulation of programmed cell death in neuronal cells by nitric oxide, In Vivo, 18, 367 Moncada, 2006, Nitric oxide, cell bioenergetics and neurodegeneration, J. Neurochem., 97, 1676, 10.1111/j.1471-4159.2006.03988.x Garthwaite, 2008, Concepts of neural nitric oxide-mediated transmission, Eur. J. Neurosci., 27, 2783, 10.1111/j.1460-9568.2008.06285.x Bredt, 1999, Endogenous nitric oxide synthesis: biological functions and pathophysiology, Free Radic. Res., 31, 577, 10.1080/10715769900301161 Calabrese, 2007, Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity, Nat. Rev. Neurosci., 8, 766, 10.1038/nrn2214 Schwarz, 1999, Potential functional significance of brain-type and muscle-type nitric oxide synthase I expressed in adventitia and media of rat aorta, Arterioscler. Thromb. Vasc. Biol., 19, 2584, 10.1161/01.ATV.19.11.2584 Xu, 1999, Nitric oxide synthase in cardiac sarcoplasmic reticulum, Proc. Natl. Acad. Sci. USA, 96, 657, 10.1073/pnas.96.2.657 Rothe, 2005, New aspects of the location of neuronal nitric oxide synthase in the skeletal muscle: a light and electron microscopic study, Nitric Oxide, 13, 21, 10.1016/j.niox.2005.04.008 McConell, 2007, Skeletal muscle nNOS mu protein content is increased by exercise training in humans, Am. J. Physiol. Regul. Integr. Comp. Physiol., 293, R821, 10.1152/ajpregu.00796.2006 Stamler, 2001, Physiology of nitric oxide in skeletal muscle, Physiol. Rev., 81, 209, 10.1152/physrev.2001.81.1.209 Lau, 2000, NNOS and eNOS modulate cGMP formation and vascular response in contracting fast-twitch skeletal muscle, Physiol. Genomics, 2, 21, 10.1152/physiolgenomics.2000.2.1.21 Santizo, 2000, Relative contributions from neuronal and endothelial nitric oxide synthases to regional cerebral blood flow changes during forebrain ischemia in rats, Neuroreport, 11, 1549, 10.1097/00001756-200005150-00036 Boissel, 1998, Neuronal-type NO synthase: transcript diversity and expressional regulation, Nitric Oxide, 2, 337, 10.1006/niox.1998.0189 Reif, 1999, Tetrahydrobiopterin inhibits monomerization and is consumed during catalysis in neuronal NO synthase, J. Biol. Chem., 274, 24921, 10.1074/jbc.274.35.24921 Sagami, 2001, Intra-subunit and inter-subunit electron transfer in neuronal nitric-oxide synthase: effect of calmodulin on heterodimer catalysis, J. Biol. Chem., 276, 30036, 10.1074/jbc.M104123200 Noguchi, 2001, Important role of tetrahydrobiopterin in no complex formation and interdomain electron transfer in neuronal nitric-oxide synthase, Biochem. Biophys. Res. Commun., 282, 1092, 10.1006/bbrc.2001.4697 Hemmens, 2000, Role of bound zinc in dimer stabilization but not enzyme activity of neuronal nitric-oxide synthase, J. Biol. Chem., 275, 35786, 10.1074/jbc.M005976200 Roman, 2006, Electron transfer by neuronal nitric-oxide synthase is regulated by concerted interaction of calmodulin and two intrinsic regulatory elements, J. Biol. Chem., 281, 23111, 10.1074/jbc.M603671200 Jiang, 2004, Differential vulnerability of immature murine neurons to oxygen-glucose deprivation, Exp. Neurol., 190, 224, 10.1016/j.expneurol.2004.07.010 Chen, 2004, The localization of neuronal nitric oxide synthase may influence its role in neuronal precursor proliferation and synaptic maintenance, Dev. Biol., 269, 165, 10.1016/j.ydbio.2004.01.024 Wang, 2008, Neuronal nitric oxide synthase signaling within cardiac myocytes targets phospholamban, Am. J. Physiol. Cell Physiol., 294, C1566, 10.1152/ajpcell.00367.2007 Yuan, 2004, Evidence of nuclear localization of neuronal nitric oxide synthase in cultured astrocytes of rats, Life Sci., 74, 3199, 10.1016/j.lfs.2003.10.037 Hecker, 1994, Subcellular localization and characterization of neuronal nitric oxide synthase, J. Neurochem., 62, 1524, 10.1046/j.1471-4159.1994.62041524.x Rothe, 1998, Subcellular localization of the neuronal isoform of nitric oxide synthase in the rat brain: a critical evaluation, Neuroscience, 83, 259, 10.1016/S0306-4522(97)00373-4 Korzhevskiĭ, 2007, Immunocytochemical demonstration of neuronal NO-synthase in rat brain cells, Morfologiia, 132, 77 Brenman, 1996, Cloning and characterization of postsynaptic density 93, a nitric oxide synthase interacting protein, J. Neurosci., 16, 7407, 10.1523/JNEUROSCI.16-23-07407.1996 Jaffrey, 2002, Neuronal nitric-oxide synthase localization mediated by a ternary complex with synapsin and CAPON, Proc. Natl. Acad. Sci. USA, 99, 3199, 10.1073/pnas.261705799 Crane, 1998, Structure of nitric oxide synthase oxygenase dimer with pterin and substrate, Science, 279, 2121, 10.1126/science.279.5359.2121 Fischmann, 1999, Structural characterization of nitric oxide synthase isoforms reveals striking active site conservation, Nat. Struct. Biol., 6, 233, 10.1038/6675 Venema, 1997, Interaction of neuronal nitric-oxide synthase with caveolin-3 in skeletal muscle. Identification of a novel caveolin scaffolding/inhibitory domain, J. Biol. Chem., 272, 28187, 10.1074/jbc.272.45.28187 Panda, 2003, Distinct influence of N-terminal elements on neuronal nitric-oxide synthase structure and catalysis, J. Biol. Chem., 278, 37122, 10.1074/jbc.M304456200 Kamada, 2005, Tetrahydrobiopterin depletion and ubiquitylation of neuronal nitric oxide synthase, Brain Res. Mol. Brain Res., 142, 19, 10.1016/j.molbrainres.2005.09.003 Lajoix, 2004, Changes in the dimeric state of neuronal nitric oxide synthase affect the kinetics of secretagogue-induced insulin response, Diabetes, 53, 1467, 10.2337/diabetes.53.6.1467 Dunbar, 2004, Ubiquitination and degradation of neuronal nitric-oxide synthase in vitro: dimer stabilization protects the enzyme from proteolysis, Mol. Pharmacol., 66, 964, 10.1124/mol.104.000125 Siddhanta, 1996, Heme iron reduction and catalysis by a nitric oxide synthase heterodimer containing one reductase and two oxygenase domains, J. Biol. Chem., 271, 7309, 10.1074/jbc.271.13.7309 Jaffrey, 1996, PIN: an associated protein inhibitor of neuronal nitric oxide synthase, Science, 274, 774, 10.1126/science.274.5288.774 El-Mlili, 2008, Chronic hyperammonemia reduces the activity of neuronal nitric oxide synthase in cerebellum by altering its localization and increasing its phosphorylation by calcium-calmodulin kinase II, J. Neurochem., 106, 1440, 10.1111/j.1471-4159.2008.05495.x Rameau, 2004, Bidirectional regulation of neuronal nitric oxide synthase phosphorylation at serine 847 by the N-methyl-d-aspartate receptor, J. Biol. Chem., 279, 4307, 10.1074/jbc.M311103200 Adak, 2001, Neuronal nitric-oxide synthase mutant (Ser-1412→Asp) demonstrates surprising connections between heme reduction, NO complex formation, and catalysis, J. Biol. Chem., 276, 1244, 10.1074/jbc.M006857200 Rameau, 2007, Biphasic coupling of neuronal nitric oxide synthase phosphorylation to the NMDA receptor regulates AMPA receptor trafficking and neuronal cell death, J. Neurosci., 27, 3445, 10.1523/JNEUROSCI.4799-06.2007 Song, 2004, Calcium/calmodulin-dependent protein kinase I inhibits neuronal nitric-oxide synthase activity through serine 741 phosphorylation, FEBS Lett., 570, 133, 10.1016/j.febslet.2004.05.083 Matsuda, 1999, Calmodulin activates intramolecular electron transfer between the two flavins of neuronal nitric oxide synthase flavin domain, Biochim. Biophys. Acta, 1473, 345, 10.1016/S0304-4165(99)00193-2 Roman, 2006, Electron transfer by neuronal nitric-oxide synthase is regulated by concerted interaction of calmodulin and two intrinsic regulatory elements, J. Biol. Chem., 281, 23111, 10.1074/jbc.M603671200 Guan, 2003, Electron transfer is activated by calmodulin in the flavin domain of human neuronal nitric oxide synthase, Arch. Biochem. Biophys., 412, 65, 10.1016/S0003-9861(03)00009-2 Dreyer, 2004, Nitric oxide synthase (NOS)-interacting protein interacts with neuronal NOS and regulates its distribution and activity, J. Neurosci., 24, 10454, 10.1523/JNEUROSCI.2265-04.2004 Nathan, 1994, Nitric oxide synthases: roles, tolls, and controls, Cell, 78, 915, 10.1016/0092-8674(94)90266-6 Yamamoto, 2004, Ca2+, calmodulin and phospholipids regulate nitric oxide synthase activity in the rabbit submandibular gland, J. Comp. Physiol. [B], 174, 593, 10.1007/s00360-004-0448-y Li, 2005, Structure-function studies on nitric oxide synthases, J. Inorg. Biochem., 99, 293, 10.1016/j.jinorgbio.2004.10.016 Cui, 2007, PDZ protein interactions underlying NMDA receptor-mediated excitotoxicity and neuroprotection by PSD-95 inhibitors, J. Neurosci., 27, 9901, 10.1523/JNEUROSCI.1464-07.2007 Chen, 2008, Involvement of CAPON and nitric oxide synthases in rat muscle regeneration after peripheral nerve injury, J. Mol. Neurosci., 34, 89, 10.1007/s12031-007-9005-y Lemaire, 2006, Binding of Vac14 to neuronal nitric oxide synthase: characterisation of a new internal PDZ-recognition motif, FEBS Lett., 580, 6948, 10.1016/j.febslet.2006.11.061 Chanrion, 2007, Physical interaction between the serotonin transporter and neuronal nitric oxide synthase underlies reciprocal modulation of their activity, Proc. Natl. Acad. Sci. USA, 104, 8119, 10.1073/pnas.0610964104 Saitoh, 2004, NIDD, a novel DHHC-containing protein, targets neuronal nitric-oxide synthase (nNOS) to the synaptic membrane through a PDZ-dependent interaction and regulates nNOS activity, J. Biol. Chem., 279, 29461, 10.1074/jbc.M401471200 Riefler, 2001, Binding of neuronal nitric-oxide synthase (nNOS) to carboxyl-terminal-binding protein (CtBP) changes the localization of CtBP from the nucleus to the cytosol: a novel function for targeting by the PDZ domain of nNOS, J. Biol. Chem., 276, 48262, 10.1074/jbc.M106503200 Sattler, 1999, Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein, Science, 284, 1845, 10.1126/science.284.5421.1845 Jaffrey, 1998, CAPON: a protein associated with neuronal nitric oxide synthase that regulates its interactions with PSD95, Neuron, 20, 115, 10.1016/S0896-6273(00)80439-0 Fang, 2000, Dexras1: a G protein specifically coupled to neuronal nitric oxide synthase via CAPON, Neuron, 28, 183, 10.1016/S0896-6273(00)00095-7 Cheah, 2006, NMDA receptor-nitric oxide transmission mediates neuronal iron homeostasis via the GTPase Dexras1, Neuron, 51, 431, 10.1016/j.neuron.2006.07.011 Moos, 2004, The metabolism of neuronal iron and its pathogenic role in neurological disease: review, Ann. NY Acad. Sci., 1012, 14, 10.1196/annals.1306.002 Firestein, 1999, Interaction of neuronal nitric-oxide synthase and phosphofructokinase-M, J. Biol. Chem., 274, 10545, 10.1074/jbc.274.15.10545 Tochio, 2000, Formation of nNOS/PSD-95 PDZ dimer requires a preformed beta-finger structure from the nNOS PDZ domain, J. Mol. Biol., 303, 359, 10.1006/jmbi.2000.4148 Christopherson, 1999, PSD-95 assembles a ternary complex with the N-methyl-d-aspartic acid receptor and a bivalent neuronal NO synthase PDZ domain, J. Biol. Chem., 274, 27467, 10.1074/jbc.274.39.27467 Rodríguez-Crespo, 1998, Binding of dynein light chain (PIN) to neuronal nitric oxide synthase in the absence of inhibition, Arch. Biochem. Biophys., 359, 297, 10.1006/abbi.1998.0928 Xia, 2006, PIN inhibits nitric oxide and superoxide production from purified neuronal nitric oxide synthase, Biochim. Biophys. Acta, 1760, 1445, 10.1016/j.bbagen.2006.04.007 Bender, 1999, Neuronal nitric-oxide synthase is regulated by the Hsp90-based chaperone system in vivo, J. Biol. Chem., 274, 1472, 10.1074/jbc.274.3.1472 Song, 2001, Heat-shock protein 90 augments neuronal nitric oxide synthase activity by enhancing Ca2+/calmodulin binding, Biochem. J., 355, 357, 10.1042/0264-6021:3550357 Bruel-Jungerman, 2007, Adult hippocampal neurogenesis, synaptic plasticity and memory: facts and hypotheses, Rev. Neurosci., 18, 93, 10.1515/REVNEURO.2007.18.2.93 Parent, 2006, Aberrant seizure-induced neurogenesis in experimental temporal lobe epilepsy, Ann. Neurol., 59, 81, 10.1002/ana.20699 Wiltrout, 2007, Repairing brain after stroke: a review on post-ischemic neurogenesis, Neurochem. Int., 50, 1028, 10.1016/j.neuint.2007.04.011 Ehninger, 2008, Neurogenesis in the adult hippocampus, Cell Tissue Res., 331, 243, 10.1007/s00441-007-0478-3 Romero-Grimaldi, 2008, Age-dependent effect of nitric oxide on subventricular zone and olfactory bulb neural precursor proliferation, J. Comp. Neurol., 506, 339, 10.1002/cne.21556 Islam, 2003, Morphological basis of nitric oxide production and its correlation with the polysialylated precursor cells in the dentate gyrus of the adult guinea pig hippocampus, Anat. Sci. Int., 78, 98, 10.1046/j.0022-7722.2003.00045.x Matarredona, 2004, Nitric oxide synthesis inhibition increases proliferation of neural precursors isolated from the postnatal mouse subventricular zone, Brain Res., 995, 274, 10.1016/j.brainres.2003.10.010 Zhu, 2006, Neuronal nitric oxide synthase-derived nitric oxide inhibits neurogenesis in the adult dentate gyrus by down-regulating cyclic AMP response element binding protein phosphorylation, Neuroscience, 141, 827, 10.1016/j.neuroscience.2006.04.032 Packer, 2003, Nitric oxide negatively regulates mammalian adult neurogenesis, Proc. Natl. Acad. Sci. USA, 100, 9566, 10.1073/pnas.1633579100 Jin, 2001, Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat, Proc. Natl. Acad. Sci. USA, 98, 4710, 10.1073/pnas.081011098 Zhou, 2007, Neuronal nitric oxide synthase contributes to chronic stress-induced depression by suppressing hippocampal neurogenesis, J. Neurochem., 103, 1843, 10.1111/j.1471-4159.2007.04914.x Zhang, 2001, A nitric oxide donor induces neurogenesis and reduces functional deficits after stroke in rats, Ann. Neurol., 50, 602, 10.1002/ana.1249 Hua, 2008, DETA/NONOate, a nitric oxide donor, produces antidepressant effects by promoting hippocampal neurogenesis, Psychopharmacology (Berlin), 200, 231, 10.1007/s00213-008-1200-1 Blackshaw, 2003, Species, strain and developmental variations in hippocampal neuronal and endothelial nitric oxide synthase clarify discrepancies in nitric oxide-dependent synaptic plasticity, Neuroscience, 119, 979, 10.1016/S0306-4522(03)00217-3 Bon, 2003, On the role of nitric oxide in hippocampal long-term potentiation, J. Neurosci., 23, 1941, 10.1523/JNEUROSCI.23-05-01941.2003 Böhme, 1993, Altered synaptic plasticity and memory formation in nitric oxide synthase inhibitor-treated rats, Proc. Natl. Acad. Sci. USA, 90, 9191, 10.1073/pnas.90.19.9191 Rickard, 2003, Effects of nitric oxide inhibition on avoidance learning in the chick are lateralized and localized, Neurobiol. Learn. Mem., 79, 252, 10.1016/S1074-7427(03)00004-2 Koylu, 2005, Effects of nitric oxide synthase inhibition on spatial discrimination learning and central DA2 and mACh receptors, Pharmacol. Biochem. Behav., 81, 32, 10.1016/j.pbb.2005.02.008 Bannerman, 1994, Inhibition of nitric oxide synthase does not impair spatial learning, J. Neurosci., 14, 7404, 10.1523/JNEUROSCI.14-12-07404.1994 Rickard, 1999, Inhibition of the endothelial isoform of nitric oxide synthase impairs long-term memory formation in the chick, Learn. Mem., 6, 458, 10.1101/lm.6.5.458 Hölscher, 1996, 7-Nitroindazole, a selective neuronal nitric oxide synthase inhibitor in vivo, impairs spatial learning in the rat, Learn. Mem., 2, 267, 10.1101/lm.2.6.267 Yildiz Akar, 2007, 7-Nitroindazole, a neuronal nitric oxide synthase inhibitor, impairs passive-avoidance and elevated plus-maze memory performance in rats, Pharmacol. Biochem. Behav., 87, 434, 10.1016/j.pbb.2007.05.019 Xu, 2001, NMDA receptor antagonist AP5 and nitric oxide synthase inhibitor 7-NI affect different phases of learning and memory in goldfish, Brain Res., 889, 274, 10.1016/S0006-8993(00)03216-9 Weitzdoerfer, 2004, Neuronal nitric oxide synthase knock-out mice show impaired cognitive performance, Nitric oxide, 10, 130, 10.1016/j.niox.2004.03.007 Kirchner, 2004, Impaired cognitive performance in neuronal nitric oxide synthase knockout mice is associated with hippocampal protein derangements, Nitric oxide, 11, 316, 10.1016/j.niox.2004.10.005 Sattler, 2000, Molecular mechanisms of calcium-dependent excitotoxicity, J. Mol. Med., 78, 3, 10.1007/s001090000077 Gardoni, 2006, New targets for pharmacological intervention in the glutamatergic synapse, Eur. J. Pharmacol., 545, 2, 10.1016/j.ejphar.2006.06.022 Arundine, 2003, Molecular mechanisms of calcium-dependent neurodegeneration in excitotoxicity, Cell Calcium, 34, 325, 10.1016/S0143-4160(03)00141-6 Eliasson, 1999, Neuronal nitric oxide synthase activation and peroxynitrite formation in ischemic stroke linked to neural damage, J. Neurosci., 19, 5910, 10.1523/JNEUROSCI.19-14-05910.1999 Oka, 2000, Involvement of peroxynitrite and hydroxyradical generated from nitric oxide in hypoxia/reoxygenation injury in rat cerebrocortical slices, Neuropharmacology, 39, 1319, 10.1016/S0028-3908(99)00197-5 Dawson, 1996, Resistance to neurotoxicity in cortical cultures from neuronal nitric oxide synthase deficient mice, J. Neurosci., 16, 2479, 10.1523/JNEUROSCI.16-08-02479.1996 Huang, 1999, Neuronal and endothelial nitric oxide synthase gene knockout mice, Braz. J. Med. Biol. Res., 32, 1353, 10.1590/S0100-879X1999001100005 Zhang, 1996, ARL 17477, a potent and selective neuronal NOS inhibitor decreases infarct volume after transient middle cerebral artery occlusion in rats, J. Cereb. Blood Flow Metab., 16, 599, 10.1097/00004647-199607000-00009 Nanri, 1998, The selective inhibitor of neuronal nitric oxide synthase, 7-nitroindazole, reduces the delayed neuronal damage due to forebrain ischemia in rats, Stroke, 29, 1248, 10.1161/01.STR.29.6.1248 Sun, 2005, Neuronal nitric oxide synthase and ischemia-induced neurogenesis, J. Cereb. Blood Flow Metab., 25, 485, 10.1038/sj.jcbfm.9600049 Luo, 2007, Reduced neuronal nitric oxide synthase is involved in ischemia-induced hippocampal neurogenesis by up-regulating inducible nitric oxide synthase expression, J. Neurochem., 103, 1872, 10.1111/j.1471-4159.2007.04915.x Abulrob, 2005, Protection by cholesterol-extracting cyclodextrins: a role for N-methyl-d-aspartate receptor redistribution, J. Neurochem., 92, 1477, 10.1111/j.1471-4159.2005.03001.x Takagi, 2000, Altered interaction between PSD-95 and the NMDA receptor following transient global ischemia, J. Neurochem., 74, 169, 10.1046/j.1471-4159.2000.0740169.x Yan, 2004, Postsynaptic density protein 95 mediates Ca2+/calmodulin-dependent protein kinase II-activated serine phosphorylation of neuronal nitric oxide synthase during brain ischemia in rat hippocampus, Neurosci. Lett., 355, 197, 10.1016/j.neulet.2003.11.001 Samdani, 1997, Nitric oxide synthase in models of focal ischemia, Stroke, 28, 1283, 10.1161/01.STR.28.6.1283 Manji, 2001, The cellular neurobiology of depression, Nat. Med., 7, 541, 10.1038/87865 Angulo, 2001, Differential effects of serotonin reuptake inhibitors on erectile responses, NO-production, and neuronal NO synthase expression in rat corpus cavernosum tissue, Br. J. Pharmacol., 134, 1190, 10.1038/sj.bjp.0704351 Harvey, 2006, Increased hippocampal nitric oxide synthase activity and stress responsiveness after imipramine discontinuation: Role of 5HT2A/C-receptors, Metab. Brain Dis., 21, 211, 10.1007/s11011-006-9018-1 Suzuki, 2001, Elevated plasma nitrate levels in depressive states, J. Affect Disord., 63, 221, 10.1016/S0165-0327(00)00164-6 F. Yildiz, B.F. Erden, G. Ulak, T. Utkan, N. Gacar, Antidepressant-like effect of 7-nitroindazole in the forced swimming test in rats, Psychopharmacology (Berlin) 149 (2000) 41–44. Kishimoto, 1996, Immobilization-induced stress activates neuronal nitric oxide synthase (nNOS) mRNA and protein in hypothalamic-pituitary-adrenal axis in rats, Brain Res., 720, 159, 10.1016/0006-8993(96)00101-1 Burns, 1983, A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine, Proc. Natl. Acad. Sci. USA, 80, 4546, 10.1073/pnas.80.14.4546 Kühn, 2003, The mouse MPTP model: gene expression changes in dopaminergic neurons, Eur. J. Neurosci., 17, 1, 10.1046/j.1460-9568.2003.02408.x Matthews, 1997, MPP+ induced substantia nigra degeneration is attenuated in nNOS knockout mice, Neurobiol. Dis., 4, 114, 10.1006/nbdi.1997.0141 Kurosaki, 2002, Role of nitric oxide synthase against MPTP neurotoxicity in mice, Neurol. Res., 24, 655, 10.1179/016164102101200717 Watanabe, 2008, Protective action of neuronal nitric oxide synthase inhibitor in the MPTP mouse model of Parkinson’s disease, Metab. Brain Dis., 23, 51, 10.1007/s11011-007-9080-3 Gatto, 2000, Overexpression of neutrophil neuronal nitric oxide synthase in Parkinson’s disease, Nitric oxide, 4, 534, 10.1006/niox.2000.0288 Selkoe, 2001, Alzheimer’s disease: genes, proteins, and therapy, Physiol. Rev., 81, 741, 10.1152/physrev.2001.81.2.741 Tran, 2003, Tyrosine nitration of a synaptic protein synaptophysin contributes to amyloid beta-peptide-induced cholinergic dysfunction, Mol. Psychiatry, 8, 407, 10.1038/sj.mp.4001240 Malinski, 2007, Nitric oxide and nitroxidative stress in Alzheimer’s disease, J. Alzheimer’s Dis., 11, 207, 10.3233/JAD-2007-11208 Simic, 2000, Bogdanovi, nNOS expression in reactive astrocytes correlates with increased cell death related DNA damage in the hippocampus and entorhinal cortex in Alzheimer’s disease, Exp. Neurol., 165, 12, 10.1006/exnr.2000.7448 Sultana, 2006, Identification of nitrated proteins in Alzheimer’s disease brain using a redox proteomics approach, Neurobiol. Dis., 22, 76, 10.1016/j.nbd.2005.10.004 Thorns, 1998, nNOS expressing neurons in the entorhinal cortex and hippocampus are affected in patients with Alzheimer’s disease, Exp. Neurol., 150, 14, 10.1006/exnr.1997.6751 Lüth, 2001, Expression of endothelial and inducible NOS-isoforms is increased in Alzheimer’s disease, in APP23 transgenic mice and after experimental brain lesion in rat: evidence for an induction by amyloid pathology, Brain Res., 913, 57, 10.1016/S0006-8993(01)02758-5 Cao, 2005, The PSD95–nNOS interface: a target for inhibition of excitotoxic p38 stress-activated protein kinase activation and cell death, J. Cell Biol., 168, 117, 10.1083/jcb.200407024