Abstract
Alzheimer’s disease (AD) has been hypothesized to be associated with oxidative stress. In this study, the expression of key oxidative stress-handling genes was studied in hippocampus, inferior parietal lobule, and cerebellum of 10 AD subjects and 10 control subjects using reverse transcriptase-polymerase chain reaction (RT-PCR). The content of Mn-, Cu,Zn-superoxide dismutases (Mn- and Cu,Zn-SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione reductase (GSSG-R) mRNAs, and the “marker genes” (β-actin and cyclophilin) mRNAs was determined. This study suggests that gene responses to oxidative stress can be significantly modulated by the general decrease of transcription in the AD brain. To determine if the particular oxidative stress handling gene transcription was induced or suppressed in AD, the “oxidative stress-handling gene/β-actin” ratios were quantified and compared with control values in all brain regions studied. The Mn-SOD mRNA/β-actin mRNA ratio was unchanged in all regions of the AD brain studied, but an increase of the Cu,Zn-SOD mRNA/β-actin mRNA ratio was observed in the AD inferior parietal lobule. The levels of peroxidation handling (CAT, GSH-Px, and GSSG-R) mRNAs normalized to β-actin mRNA level were elevated in hippocampus and inferior parietal lobule, but not in cerebellum of AD patients, which may reflect the protective gene response to the increased peroxidation in the brain regions showing severe AD pathology. The results of this study suggest that region-specific differences of the magnitude of ROS-mediated injury rather than primary deficits of oxidative stress handling gene transcription are likely to contribute to the variable intensity of neurodegeneration in different areas of AD brain.
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Aksenova M. V., Aksenov M. Y., Payne R. M., Trojanowski J. Q., Schmidt M. L., Butterfield D. A., and Markesbery W. R. (1999) Oxidation of cytosolic proteins and expression of creatine kinase BB in frontal lobe in different neurodegenerative disorders. Dementia, in press.
Balazs L. and Leon M. (1994) Evidence of an oxidative challenge in the Alzheimer’s brain. Neurochem. Res. 19, 1131–1137.
Beal M. F. (1995) Aging, energy, and oxidative stress in neurodegenerative diseases. Ann. Neurol. 38, 357–366.
Benzi G. and Moretti A. (1995) Are reactive oxygen species involved in Alzheimer’s disease. Neurobiol. Aging 16, 661–664.
Behl C. and Sagara Y. (1997) Mechanism of amyloid beta protein induced neuronal cell death, current concepts and future perspectives. J. Neural Trans. Suppl. 49, 125–134.
Bowling A. C. and Beal M. F. (1995) Bioenergetic and oxidative stress in neurodegenerative diseases. Life Sciences. 56, 1151–1171.
Butterfield D. A. (1997) b-Amyloid-associated free radical oxidative stress and neurotoxicity, implications for Alzheimer’s disease. Chem. Res. Toxicol. 10, 495–506.
Butterfield D. A. and Stadtman E. R. (1997) Protein oxidation processes in aging brain, in Advances in Cell Aging and Gerontology, vol. 2 (Mattson, M. P. and Geddes J. W., eds.), JAI Press, Greenwich, CT, 161–191.
Cavelier L., Jazzin E. E., Eriksson I., Prince J., Bave U., Oreland L., and Gyllensten U. (1995) Decreased cytochrome-c oxidase activity and lack of agerelated accumulation of mitochondrial DNA deletions in the brains of schizophrenics. Genomics 289, 217–224.
Chen L., Richardson J., Caldwell J., and Ang L. (1994) Regional brain activity of free radical defense enzymes in autopsy samples from patients with Alzheimer’s disease and from nondemented controls. Int. J. Neurosci. 75, 83–90.
Chromzynski P. and Sacchi N. (1987) Single-step method of RNA isolation by acid guanidinum thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162, 156–159.
Colton C. A., Snell J., Chernyshev O., and Gilbert D. L. (1994) Induction of superoxide anion and nitric oxide production in cultural microglia. Ann. NY Acad. Sci. 78, 54–63.
Coyle J. T. and Puttfarcken P. (1993) Oxidative stress, glutamate, and neurodegenerative disorders. Science 262, 689–695.
Crapper McLachlan D. R., Lukiw W. J., Wong L., Bergeron C., and Bech-Hansen N. T. (1988) Selective messenger RNA reduction in Alzheimer’s disease. Mol. Brain Res. 15, 681–690.
Davis J. B. (1996) Oxidative mechanisms in beta-amyloid cytotoxicity. Neurodegeneration. 5, 441–444.
Desagher S., Glowinski J., and Premont J. (1996) Astrocytes protect neurons from hydrogen peroxide toxicity. J. Neurosci. 16, 2553–2562.
Estus S. (1997) Optimization and validation of RT-PCR as a tool to analyze apoptotic gene expression, in Neuromethods, vol. 29: Apoptosis Techniques and Protocols (Poirier J., ed.), Humana, Totowa, NJ, pp. 67–84.
Furuta A., Price D. L., Pardo C. A., Troncoso J. C., Xu Z. S., Taniguchi N., and Martin L. J. (1995) Localization of superoxide dismutases in Alzheimer’s disease and Down’s syndrome neocortex and hyppocampus. Am. J. Pathol. 146, 357–367.
Gabbita P. S., Lovell M. A., and Markesbery W. R. (1998) Increased nuclear DNA oxidation in the brain in Alzheimer’s disease. J. Neurochem. 71, 2034–2040.
Gerlach M., Ben-Shachar D., Riederer P., and Youdim B. H. (1994) Altered brain metabolism of iron as a cause of neurodegenerative diseases? J. Neurochem. 63, 793–807.
Greenlund L. J. S., Deckwerth T. L., and Johnson J. E. Jr. (1995) Superoxide dismutase delays neuronal apoptosis, a role for oxygen species in programmed neuronal death. Neuron 14, 303–315.
Gsell W., Conrad R., Hickethier M., Sofic E., Frolich L., Wichart I., et al. (1995) Decreased catalase activity but unchanged superoxide dismutase activity in brains of patients with dementia of Alzheimer type. J. Neurochem. 64, 1216–1223.
Guillemette J. G., Wong L., Crapper McLachlan D. R., and Lewis P. N. (1987) Characterization of messenger RNA from the cerebral cortex of control and Alzheimer-afflicted brain. J. Neurochem. 47, 987–997.
Harman D. (1995) Free radical theory of aging, Alzheimer’s disease pathogenesis. Age 18, 97–119.
Hensley K., Butterfield D. A., Hall N., Cole P., Subramaniam R., Mark R., et al. (1996) Reactive oxygen species as casual agents in the neurotoxicity of the Alzheimer’s disease-associated amyloid beta peptide. Ann. NY Acad. Sci. 786, 120–134.
Hensley K., Hall N., Subramaniam R., Cole P., Harris M., Aksenov M., et al. (1995) Brain regional correspondence between Alzheimer’s disease histopathology and biomarkers of protein oxidation. J. Neurochem. 65, 2146–2156.
Hoyer S. (1993) Brain oxidative energy and related metabolism, neuronal stress and Azheimer’s disease, A speculative synthesis. J. Geriatr. Psychiatry Neurol. 6, 3–13.
Hoyt K. R., Gallagher A. J., Hastings T. G., and Reinolds I. J. (1997) Characterization of hydrogen peroxide toxicity in cultured rat forebrain neurons. Neurochem. Res. 22, 333–340.
Kaltshmidt B., Uherek M., Volk B., Baeuerie P. A., and Kaltschmidt C. (1997) Transcription factor NF-kappaB is activated in primary neurons by amyloid beta peptides and in neurons surrounding early plaques from patients with Alzheimer disease. Proc. Natl. Acad. Sci. USA 94, 2642–2647.
Kato K., Kurobe N., Suzaki R., Morishita R., Asano T., Sato T., and Inagaki T. (1991) Concentrations of several proteins characteristic of nervous tissue in cerebral cortex of patients with Alzheimer’s disease. J. Mol. Neurosci. 3, 95–99.
Khachaturian Z. S. (1985) Diagnosis of Alzheimer’s disease. Arch. Neurol. 42, 1097–1105.
Knezetic J. A. and Luse D. S. (1986) The presence of nucleosomes on a DNA template prevents initiation by RNA II polymerase in vitro. Cell 45, 95–104.
Komori N., Kittel A., Kang D., Shackelford D., Masliah E., Zivin J. A., and Saitoh T. (1997) Reversible ischemia increases levels of Alzheimer amyloid protein precusor without increasing levels of mRNA in the rabbit spinal cord. Brain Res. Mol. Brain Res. 49, 103–112.
Krowzynska A., Yenofsky R., and Brawerman G. (1985) Regulation of messenger RNA stability in mouse erythroleukemia cells. J. Mol. Biol. 181, 231–239.
Lewis P. N., Lukiw W. J., De Boni U., and Crapper McLachlan D. R. (1981) Changes in chromatin structure associated with Alzheimer’s disease. J. Neurochem. 37, 1193–1202.
Lovell M. A., Ehmann W. D., Butler S. M., and Markesbery W. R. (1995) Elevated thiobarbituric acid-reactive substances and antioxidant enzyme activity in the brain in Alzheimer’s disease. Neurology 45, 1594–1601.
Lukiw W. J. and Crapper McLachlan D. R. (1990) Chromatin structure and gene expression in Alzheimer’s disease. Mol. Brain. Res. 7, 227–234.
Maeda M., Takagi H., Hattori H., and Matsuzaki T. (1997) Localization of manganese superoxide dismutase in cerebral cortex and hippocampus of Alzheimer-type senile dementia. Osaka City Med. J. 43, 1–5.
Mattson M. P., Goodman Y., Luo H, Fu W., and Furukawa K. (1997) Activation of NF-kappaB protects hippocampal neurons against oxidative stress-induced apoptosis, evidence for induction of manganese superoxide dismutase and suppression of peroxinitrite production and protein tyrosine nitration. J. Neurosci. Res. 49, 681–697.
Marcus D. L., Thomas C., Rodriguez C., Simberkoff K., Tsai J. S., Strafaci J. A., and Freedman M. L. (1998) Increased peroxidation and reduced antioxidant activity in Alzheimer’s disease. Exp. Neurology. 150, 40–44.
Markesbery W. R. (1997) Oxidative stress hypothesis in Alzheimer’s disease. Free Radic. Biol. Med. 23, 134–147.
Markesbery W. R. and Lovell M. A. (1998) Four-hydroxynoneal, a product of lipid peroxidation, is increased in the brain in Alzheimer’s disease. Neurobiol. Aging 19, 33–36.
Markesbery W. R. and Ehmann W. D. (1993) Brain trace elements in Alzheimer disease, in Alzheimer Disease (Terry R. D., Katzman R., and Bick K. L., eds.), Raven, New York, pp. 353–367.
Marklund S. L., Adolfsson R., Gottfries C. G., and Winblad B. (1985) Superoxide dismutase isoenzymes in normal brains and in brains from patients with dementia of Alzheimer type. J. Neurol. Sci. 67, 319–325.
McKhann G., Drachman D., Folstein M., Katzman R., Price D., and Stadlan E. M. (1984) Clinical diagnosis of Alzheimer’s disease, report of the NINCDS ADRDA work group under the aupsies of Department of Health and Human Services Task Force on Alzheimer’s disease. Neurology 34, 939–944.
Mecocci P., MacGarvey U., and Beal M. F. (1994) Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease. Ann. Neurol. 36, 747–751.
Mecocci P., Beal M. F., Cecchetti R., Polidori M. C., Cherubini A., Chionne F., et al. (1997) Mitochondrial membrane fluidity and oxidative damage to mitochondrial DNA in aged and AD human brain. Mol. Chem. Neuropathol. 31, 53–64.
Mirra S. S., Heyman A., and McKeel D. (1991) The Consorcium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standartization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41, 479–486.
National Institute on Aging and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assesment of Alzheimer’s disease. (1997) Consensus recomendations. Neurobiol. Aging S1,S2.
Nutisya E. M., Bowling A. C., and Beal M. F. (1994) Cortical cytochrome oxidase activity is reduced in Alzheimer’s disease. J. Neurochem. 63, 2179–2184.
Palmer H. J. and Paulson K. E. (1997) Reactive oxygen species and antioxidants in signal transduction and gene expression. Nutr. Rev. 55, 353–361.
Parker W. D., Parks J. Jr., Filley C. M., and Kleinschmidt-Demasters B. K. (1994) Electron transport chain defects in Alzheimer’s disease brain. Neurology 44, 1090–1096.
Rajagopalan L. E. and Malter J. S. (1997) Regulation of eucariotic messenger RNA turnover. Prog. Nucleic Acid Res. Mol. Biol. 56, 257–286.
Richardson J. S. (1993) Free radicals in the genesis of Alzheimer’s disease. Ann. N Y Acad. Sci. 695, 73–76.
Sagara Y., Dargusch R., Klier F. G., Schubert D., and Behl C. (1996) Increased antioxidant enzyme activity in amyloid beta protein-resistant cells. J. Neurosci. 16, 497–505.
Sajdel-Sulkowska E. M. and Marotta C. A. (1984) Alzheimer’s disease brain, alterations in RNA levels and in a ribonuclease-inhibitor complex. Science 225, 947–949.
Sambrook J., Fritsch E. F., and Maniatis T. (1982) Molecular Cloning, A Laboratory Manual. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY.
Selkoe D. J. (1991) The molecular pathology of Alzheimer’s disease. Neuron 61, 487–498.
Sheehan J. P., Swerdlow R. H., Miller S. W., Davis R. E., Parks J. K., and Tuttle J. B. (1997) Calcium homeostasis and reactive oxygen species production in cells transformed by mitochondria from individuals with sporadic Azheimer’s disease. J. Neurosci. 17, 4612–4622.
Simonian N. A. and Coyle J. T. (1996) Oxidative stress in neurodegenerative diseases. Annu. Rev. Pharmacol. Toxicol. 36, 83–106.
Smith M. A., Perry G., Richey P. L., Sayre L. M., Anderson V. E., Beal M. F., and Kowall N. (1996) Oxidative damage in Alzheimer’s. Nature 382, 120,121.
Smith M. A., Taneda S., Richey P. L., Miyata S., Yan S.-D., Stern D., and Sayre L. M. (1994) Advanced Maillard reaction end products are associated with Alzheimer disease pathology. Proc. Natl. Acad. Sci. USA 91, 5710–5714.
Sommerville M. J., Percy M. E., Bergeron C., Yoong L. K., Grima E. A., and McLachlan D. R. (1991) Localization and quantitation of 68 kDa neurofilament and superoxide dismutase-1 mRNA in Alzheimer brains. Brain Res. Mol. Brain Res. 9, 1–8.
Subbarao K. V., Richardson J. S., and Ang L. C. (1990) Autopsy samples of Alzheimer’s cortex show increased peroxidation in vitro. J. Neurochem. 55, 342–345.
Taylor G. R., Carte G. I., Grow T. J., Johnson J. A., Fairbairn A. F., Perry E. K., and Perry R. H. (1986) Recovery and measurement of specific RNA species from postmortem brain tissue, A general reduction in Alzheimer’s disease detected by molecular hybridization. Exper. Mol. Pathol. 44, 111–116.
Whittemore E. R., Loo D. T., and Cotman C. W. (1994) Exposure to hydrogen peroxide induces cell death via apoptosis in cultured rat cortical neurons. NeuroReport 5, 1485–1488.
Wilson J. X. (1997) Antioxidant defense of the brain, a role for astrocytes. Can. J. Physiol. Pharmacol. 75, 1149–1163.
Yagi K., Komura S., Kojima H., Sun Q., Nagata N., Ohishi N., and Nishikimi M. (1996) Expression of human phospholipid hydroperoxide glutathione peroxidase gene for protection of host cells from lipid hydroperoxide-mediated injury. Biochem. Biophys. Res. Commun. 219, 486–491.
Zhou Y., Richardson J. S., Mombourquette M. J., and Weil J. A. (1995) Free radical formation in autopsy samples of Alzheimer and control cortex. Neurosci. Lett. 195, 89–92.
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Aksenov, M.Y., Tucker, H.M., Nair, P. et al. The expression of key oxidative stress-handling genes in different brain regions in alzheimer’s disease. J Mol Neurosci 11, 151–164 (1998). https://doi.org/10.1385/JMN:11:2:151
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DOI: https://doi.org/10.1385/JMN:11:2:151