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American Journal of Pathology, Vol 149, 21-28, Copyright © 1996 by American Society for Investigative Pathology
REGULAR ARTICLES |
PF Good, P Werner, A Hsu, CW Olanow and DP Perl
Department of Pathology, Mount Sinai School of Medicine, New York, New York, USA.
Oxidative stress has been proposed as a pathogenetic mechanism in Alzheimer's disease. One mechanism of oxidative damage is the nitration of tyrosine residues in proteins, mediated by peroxynitrite breakdown. Peroxynitrite, a reaction product of nitric oxide and superoxide radicals, has been implicated in N-methyl-D-aspartate receptor-mediated excitotoxic damage. Reported evidence of oxidative stress in Alzheimer's disease includes increased iron, alterations in protective enzymes, and markers of oxidative damage to proteins and lipids. In this report, we demonstrate the presence of nitrotyrosine in neurofibrillary tangles of Alzheimer's disease. Nitrotyrosine was not detected in controls lacking neurofibrillary tangles. Immunolabeling was demonstrated to be specific nitrotyrosine in a series of control experiments. These observations link oxidative stress with a key pathological lesion of Alzheimer's disease, the neurofibrillary tangle, and demonstrate a pathogenetic mechanism in common with the other major neurodegenerative diseases of aging, Parkinson's disease and amyotrophic lateral sclerosis. These findings further implicate nitric oxide expression and excitotoxicity in the pathogenesis of cell death in Alzheimer's disease.
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J. Ara, S. Przedborski, A. B. Naini, V. Jackson-Lewis, R. R. Trifiletti, J. Horwitz, and H. Ischiropoulos Inactivation of tyrosine hydroxylase by nitration following exposure to peroxynitrite and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) PNAS, June 23, 1998; 95(13): 7659 - 7663. [Abstract] [Full Text] [PDF]
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T. P. Misko, M. K. Highkin, A. W. Veenhuizen, P. T. Manning, M. K. Stern, M. G. Currie, and D. Salvemini Characterization of the Cytoprotective Action of Peroxynitrite Decomposition Catalysts J. Biol. Chem., June 19, 1998; 273(25): 15646 - 15653. [Abstract] [Full Text] [PDF]
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D. R. McDonald, M. E. Bamberger, C. K. Combs, and G. E. Landreth beta -Amyloid Fibrils Activate Parallel Mitogen-Activated Protein Kinase Pathways in Microglia and THP1 Monocytes J. Neurosci., June 15, 1998; 18(12): 4451 - 4460. [Abstract] [Full Text] [PDF]
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A. G. Estevez, N. Spear, J. A. Thompson, T. L. Cornwell, R. Radi, L. Barbeito, and J. S. Beckman Nitric Oxide-Dependent Production of cGMP Supports the Survival of Rat Embryonic Motor Neurons Cultured with Brain-Derived Neurotrophic Factor J. Neurosci., May 15, 1998; 18(10): 3708 - 3714. [Abstract] [Full Text] [PDF]
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D. Salvemini, Z.-Q. Wang, M. K. Stern, M. G. Currie, and T. P. Misko Peroxynitrite decomposition catalysts: Therapeutics for peroxynitrite-mediated pathology PNAS, March 3, 1998; 95(5): 2659 - 2663. [Abstract] [Full Text] [PDF]
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A. G. Estevez, N. Spear, S. M. Manuel, R. Radi, C. E. Henderson, L. Barbeito, and J. S. Beckman Nitric Oxide and Superoxide Contribute to Motor Neuron Apoptosis Induced by Trophic Factor Deprivation J. Neurosci., February 1, 1998; 18(3): 923 - 931. [Abstract] [Full Text] [PDF]
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D. C. Hooper, S. Spitsin, R. B. Kean, J. M. Champion, G. M. Dickson, I. Chaudhry, and H. Koprowski Uric acid, a natural scavenger of peroxynitrite, in experimental allergic encephalomyelitis and multiple sclerosis PNAS, January 20, 1998; 95(2): 675 - 680. [Abstract] [Full Text] [PDF]
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S. S. Marla, J. Lee, and J. T. Groves Peroxynitrite rapidly permeates phospholipid membranes PNAS, December 23, 1997; 94(26): 14243 - 14248. [Abstract] [Full Text] [PDF]
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J. H. Morrison and P. R. Hof Life and Death of Neurons in the Aging Brain Science, October 17, 1997; 278(5337): 412 - 419. [Abstract] [Full Text]
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M. A. Ciorba, S. H. Heinemann, H. Weissbach, N. Brot, and T. Hoshi Modulation of potassium channel function by methionine oxidation and reduction PNAS, September 2, 1997; 94(18): 9932 - 9937. [Abstract] [Full Text] [PDF]
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M. R. Gunther, L. C. Hsi, J. F. Curtis, J. K. Gierse, L. J. Marnett, T. E. Eling, and R. P. Mason Nitric Oxide Trapping of the Tyrosyl Radical of Prostaglandin H Synthase-2 Leads to Tyrosine Iminoxyl Radical and Nitrotyrosine Formation J. Biol. Chem., July 4, 1997; 272(27): 17086 - 17090. [Abstract] [Full Text] [PDF]
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