Search tips
Search criteria 


Logo of jexpmedHomeThe Rockefeller University PressEditorsContactInstructions for AuthorsThis issue
J Exp Med. 1996 October 1; 184(4): 1425–1433.
PMCID: PMC2192831

Inducible nitric oxide synthase in tangle-bearing neurons of patients with Alzheimer's disease


In Alzheimer's disease (AD), affected neurons accumulate beta amyloid protein, components of which can induce mouse microglia to express the high-output isoform of nitric oxide synthase (NOS2) in vitro. Products of NOS2 can be neurotoxic. In mice, NOS2 is normally suppressed by transforming growth factor beta 1 (TGF-beta 1). Expression of TGF-beta 1 is decreased in brains from AD patients, a situation that might be permissive for accumulation of NOS2. Accordingly, we investigated the expression of NOS2 in patients with AD, using three monospecific antibodies: a previously described polyclonal and two new monoclonal antibodies. Neurofibrillary tangle-bearing neurons and neuropil threads contained NOS2 in brains from each of 11 AD patients ranging in age from 47 to 81 years. NOS2 was undetectable in brains from 6 control subjects aged 23-72 years, but was expressed in small amounts in 3 control subjects aged 77-87 years. Thus, human neurons can express NOS2 in vivo. The high-output pathway of NO production may contribute to pathogenesis in AD.

Full Text

The Full Text of this article is available as a PDF (7.6M).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Terry RD. Neuropathological changes in Alzheimer disease. Prog Brain Res. 1994;101:383–390. [PubMed]
  • Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F, et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature. 1995 Feb 9;373(6514):523–527. [PubMed]
  • Hu J, el-Fakahany EE. beta-Amyloid 25-35 activates nitric oxide synthase in a neuronal clone. Neuroreport. 1993 Jun;4(6):760–762. [PubMed]
  • Meda L, Cassatella MA, Szendrei GI, Otvos L, Jr, Baron P, Villalba M, Ferrari D, Rossi F. Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature. 1995 Apr 13;374(6523):647–650. [PubMed]
  • Merrill JE, Ignarro LJ, Sherman MP, Melinek J, Lane TE. Microglial cell cytotoxicity of oligodendrocytes is mediated through nitric oxide. J Immunol. 1993 Aug 15;151(4):2132–2141. [PubMed]
  • Ding A, Nathan CF, Graycar J, Derynck R, Stuehr DJ, Srimal S. Macrophage deactivating factor and transforming growth factors-beta 1 -beta 2 and -beta 3 inhibit induction of macrophage nitrogen oxide synthesis by IFN-gamma. J Immunol. 1990 Aug 1;145(3):940–944. [PubMed]
  • Vodovotz Y, Bogdan C. Control of nitric oxide synthase expression by transforming growth factor-beta: implications for homeostasis. Prog Growth Factor Res. 1994;5(4):341–351. [PubMed]
  • Vodovotz Y, Geiser AG, Chesler L, Letterio JJ, Campbell A, Lucia MS, Sporn MB, Roberts AB. Spontaneously increased production of nitric oxide and aberrant expression of the inducible nitric oxide synthase in vivo in the transforming growth factor beta 1 null mouse. J Exp Med. 1996 May 1;183(5):2337–2342. [PMC free article] [PubMed]
  • Finch CE, Laping NJ, Morgan TE, Nichols NR, Pasinetti GM. TGF-beta 1 is an organizer of responses to neurodegeneration. J Cell Biochem. 1993 Dec;53(4):314–322. [PubMed]
  • Prehn JH, Peruche B, Unsicker K, Krieglstein J. Isoform-specific effects of transforming growth factors-beta on degeneration of primary neuronal cultures induced by cytotoxic hypoxia or glutamate. J Neurochem. 1993 May;60(5):1665–1672. [PubMed]
  • Prehn JH, Bindokas VP, Marcuccilli CJ, Krajewski S, Reed JC, Miller RJ. Regulation of neuronal Bcl2 protein expression and calcium homeostasis by transforming growth factor type beta confers wide-ranging protection on rat hippocampal neurons. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12599–12603. [PubMed]
  • Poulsen KT, Armanini MP, Klein RD, Hynes MA, Phillips HS, Rosenthal A. TGF beta 2 and TGF beta 3 are potent survival factors for midbrain dopaminergic neurons. Neuron. 1994 Nov;13(5):1245–1252. [PubMed]
  • Young MR, Farietta T, Crayton JW. Production of nitric oxide and transforming growth factor-beta in developing and adult rat brain. Mech Ageing Dev. 1995 Apr 14;79(2-3):115–126. [PubMed]
  • Flanders KC, Lippa CF, Smith TW, Pollen DA, Sporn MB. Altered expression of transforming growth factor-beta in Alzheimer's disease. Neurology. 1995 Aug;45(8):1561–1569. [PubMed]
  • Peress NS, Perillo E. Differential expression of TGF-beta 1, 2 and 3 isotypes in Alzheimer's disease: a comparative immunohistochemical study with cerebral infarction, aged human and mouse control brains. J Neuropathol Exp Neurol. 1995 Nov;54(6):802–811. [PubMed]
  • McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984 Jul;34(7):939–944. [PubMed]
  • Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, van Belle G, Berg L. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology. 1991 Apr;41(4):479–486. [PubMed]
  • Nicholson S, Bonecini-Almeida M da G, Lapa e Silva JR, Nathan C, Xie QW, Mumford R, Weidner JR, Calaycay J, Geng J, Boechat N, et al. Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients with tuberculosis. J Exp Med. 1996 May 1;183(5):2293–2302. [PMC free article] [PubMed]
  • Geller DA, Lowenstein CJ, Shapiro RA, Nussler AK, Di Silvio M, Wang SC, Nakayama DK, Simmons RL, Snyder SH, Billiar TR. Molecular cloning and expression of inducible nitric oxide synthase from human hepatocytes. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3491–3495. [PubMed]
  • Hall AV, Antoniou H, Wang Y, Cheung AH, Arbus AM, Olson SL, Lu WC, Kau CL, Marsden PA. Structural organization of the human neuronal nitric oxide synthase gene (NOS1). J Biol Chem. 1994 Dec 30;269(52):33082–33090. [PubMed]
  • Marsden PA, Schappert KT, Chen HS, Flowers M, Sundell CL, Wilcox JN, Lamas S, Michel T. Molecular cloning and characterization of human endothelial nitric oxide synthase. FEBS Lett. 1992 Aug 3;307(3):287–293. [PubMed]
  • Dighiero P, Reux I, Hauw JJ, Fillet AM, Courtois Y, Goureau O. Expression of inducible nitric oxide synthase in cytomegalovirus-infected glial cells of retinas from AIDS patients. Neurosci Lett. 1994 Jan 17;166(1):31–34. [PubMed]
  • Bukrinsky MI, Nottet HS, Schmidtmayerova H, Dubrovsky L, Flanagan CR, Mullins ME, Lipton SA, Gendelman HE. Regulation of nitric oxide synthase activity in human immunodeficiency virus type 1 (HIV-1)-infected monocytes: implications for HIV-associated neurological disease. J Exp Med. 1995 Feb 1;181(2):735–745. [PMC free article] [PubMed]
  • Bö L, Dawson TM, Wesselingh S, Mörk S, Choi S, Kong PA, Hanley D, Trapp BD. Induction of nitric oxide synthase in demyelinating regions of multiple sclerosis brains. Ann Neurol. 1994 Nov;36(5):778–786. [PubMed]
  • Hooper DC, Ohnishi ST, Kean R, Numagami Y, Dietzschold B, Koprowski H. Local nitric oxide production in viral and autoimmune diseases of the central nervous system. Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5312–5316. [PubMed]
  • Dorheim MA, Tracey WR, Pollock JS, Grammas P. Nitric oxide synthase activity is elevated in brain microvessels in Alzheimer's disease. Biochem Biophys Res Commun. 1994 Nov 30;205(1):659–665. [PubMed]
  • Hyman BT, Marzloff K, Wenniger JJ, Dawson TM, Bredt DS, Snyder SH. Relative sparing of nitric oxide synthase-containing neurons in the hippocampal formation in Alzheimer's disease. Ann Neurol. 1992 Dec;32(6):818–820. [PubMed]
  • Kowall NW, Beal MF. Cortical somatostatin, neuropeptide Y, and NADPH diaphorase neurons: normal anatomy and alterations in Alzheimer's disease. Ann Neurol. 1988 Feb;23(2):105–114. [PubMed]
  • Wink DA, Hanbauer I, Krishna MC, DeGraff W, Gamson J, Mitchell JB. Nitric oxide protects against cellular damage and cytotoxicity from reactive oxygen species. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):9813–9817. [PubMed]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press