Abstract
Increased oxidative damage is a prominent and early feature of vulnerable neurons in Alzheimer's disease (AD). However, while damage to proteins, sugars, lipids, nucleic acids and organelles such as lysosomes, mitochondria, and endoplasmic reticulum are evident, the source of increased reactive oxygen species has not been determined. Furthermore, a major limitation in further determining the source, as well as finding a means to arrest damage, is the paucity of cellular models directly homologous to AD since the vulnerable neurons of the brain in AD cannot be studied in vitro. Here, we examined the olfactory epithelium in situ to see if neurons there exhibit a similar pathological oxidative balance to vulnerable neurons in AD. In biopsy specimens, (eight AD and three controls) we found that neurons, and also the surrounding epithelial cells, show an increase in oxidative damage for a subset of the markers increased in the brain of cases of AD. Lipid peroxidation and heme oxygenase-1, a stress response protein, were increased, while nucleic acid or protein oxidation, demonstrated in vulnerable neurons in AD, were not increased. These findings highlight the systemic nature of oxidative abnormalities in AD, but that different cell types may express this abnormality by a different array of oxidative stress markers, supporting the potential for using olfactory neurons or other cells derived from AD patients in culture to understand the mechanistic basis for increased oxidative damage in AD and as a model to screen compounds for therapeutic intervention.
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References
Aliev G, Smith MA, Seyidova D, Neal ML, Lamb BT, Nunomura A, Gasimov EK, Vinters HV, Perry G, LaManna JC, Friedland RP (2002) The role of oxidative stress in the pathophysiology of cerebrovascular lesions in Alzheimer's disease. Brain Pathol 12:21–35
Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259
Calingasan NY, Uchida K, Gibson GE (1999) Protein-bound acrolein: a novel marker of oxidative stress in Alzheimer's disease. J Neurochem 72:751-756
Cardoso SM, Santos S, Swerdlow RH, Oliveira CR (2001) Functional mitochondria are required for amyloid beta-mediated neurotoxicity. FASEB J 15:1439–1441
Castellani RJ, Harris PLR, Sayre LM, Fujii J, Taniguchi N, Vitek MP, Founds H, Atwood CS, Perry G, Smith MA (2001) Advanced glycation in neurofibrillary pathology of Alzheimer disease: Nε-(carboxymethyl) lysine and hexitol-lysine. Free Radic Biol Med 31:175–180
Devanand DP, Michaels-Marston KS, Liu X, Pelton GH, Padilla M, Marder K, Bell K, Stern Y, Mayeux R (2000) Olfactory deficits in patients with mild cognitive impairment predict Alzheimer's disease at follow-up. Am J Psychiatry 157:1399–1405
Gabbita SP, Lovell MA, Markesbery WR (1998) Increased nuclear DNA oxidation in the brain in Alzheimer's disease. J Neurochem 71:2034–2040
Good PF, Werner P, Hsu A, Olanow CW, Perl DP (1996) Evidence of neuronal oxidative damage in Alzheimer's disease. Am J Pathol 149:21–28
Graves AB, Bowen JD, Rajaram L, McCormick WC, McCurry SM, Schellenberg GD, Larson EB (1999) Impaired olfaction as a marker for cognitive decline: interaction with apolipoprotein E ε4 status. Neurology 53:1480–1487
Koss E, Weiffenbach JM, Haxby JV, Friedland RP (1988) Olfactory detection and identification performance are dissociated in early Alzheimer's disease. Neurology 38:1228–1232
Kovacs T, Cairns NJ, Lantos PL (1999) β-Amyloid deposition and neurofibrillary tangle formation in the olfactory bulb in ageing and Alzheimer's disease. Neuropathol Appl Neurobiol 25:481–491
Kovacs T, Cairns NJ, Lantos PL (2001) Olfactory centres in Alzheimer's disease: olfactory bulb is involved early in Braak stages. Neuroreport 12:285–288
Lee JH, Goedert M, Hill WD, Lee VM, Trojanowski JQ (1993) Tau proteins are abnormally expressed in olfactory epithelium of Alzheimer patients and developmentally regulated in human fetal spinal cord. Exp Neurol 121:93–105
Markesbery WR (1997) Oxidative stress hypothesis in Alzheimer's disease. Free Radic Biol Med 23:134–147
Martzke JS, Kopala LC, Good KC (1997) Olfactory dysfunction in neuropsychiatric disorders: review and methodological considerations. Biol Psychiatry 42:721–732
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) 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 34:939–944
Neter J, Kutner MH, Nachtsheim CJ, Wasserman W (1996) Applied linear statistical methods, 4th edn. Irwin, Chicago
Nunomura A, Perry G, Pappolla MA, Wade R, Hirai K, Chiba S, Smith MA (1999) RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer's disease. J Neurosci 19:1959–1964
Nunomura A, Perry G, Pappolla MA, Friedland RP, Hirai K, Chiba S, Smith MA (2000) Neuronal oxidative stress precedes amyloid-β deposition in Down syndrome. J Neuropathol Exp Neurol 59:1011–1017
Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA (2001) Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 60:759–767
Odetti P, Garibaldi S, Norese R, Angelini G, Marinelli L, Valentini S, Menini S, Traverso N, Zaccheo D, Siedlak S, Perry G, Smith MA, Tabaton M (2000) Lipoperoxidation is selectively involved in progressive supranuclear palsy. J Neuropathol Exp Neurol 59:393–397
Pearson RC, Esiri MM, Hiorns RW, Wilcock GK, Powell TP (1985) Anatomical correlates of the distribution of the pathological changes in the neocortex in Alzheimer disease. Proc Natl Acad Sci USA 82:4531–4534
Perry G, Kawai M, Tabaton M, Onorato M, Mulvihill P, Richey P, Morandi A, Connolly JA, Gambetti P (1991) Neuropil threads of Alzheimer's disease show a marked alteration of the normal cytoskeleton. J Neurosci 11:1748–1755
Perry G, Castellani RJ, Hirai K, Smith MA (1998) Reactive oxygen species mediate cellular damage in Alzheimer disease. J Alzheimers Dis 1:45–55
Reyes PF, Golden GT, Fagel PL, Fariello RG, Katz L, Carner E (1987) The prepiriform cortex in dementia of the Alzheimer type. Arch Neurol 44:644–645
Reyes PF, Deems DA, Suarez MG (1993) Olfactory-related changes in Alzheimer's disease: a quantitative neuropathologic study. Brain Res Bull 32:1–5
Sayre LM, Sha W, Xu G, Kaur K, Nadkarni D, Subbanagounder G, Salomon RG (1996) Immunochemical evidence supporting 2-pentylpyrrole formation on proteins exposed to 4-hydroxy-2-nonenal. Chem Res Toxicol 9:1194–1201
Sayre LM, Zelasko DA, Harris PLR, Perry G, Salomon RG, Smith MA (1997) 4-Hydroxynonenal-derived advanced lipid peroxidation end products are increased in Alzheimer's disease. J Neurochem 68:2092–2097
Serby M, Larson P, Kalkstein D (1991) The nature and course of olfactory deficits in Alzheimer's disease. Am J Psychiatry 148:357–360
Sheu KF, Cooper AJ, Koike K, Koike M, Lindsay JG, Blass JP (1994) Abnormality of the α-ketoglutarate dehydrogenase complex in fibroblasts from familial Alzheimer's disease. Ann Neurol 35:312–318
Smith MA, Kutty RK, Richey PL, Yan S-D, Stern D, Chader GJ, Wiggert B, Petersen RB, Perry G (1994) Heme oxygenase-1 is associated with the neurofibrillary pathology of Alzheimer's disease. Am J Pathol 145:42–47
Smith MA, Taneda S, Richey PL, Miyata S, Yan S-D, Stern D, Sayre LM, Monnier VM, Perry G (1994) Advanced Maillard reaction end products are associated with Alzheimer disease pathology. Proc Natl Acad Sci USA 91:5710–5714
Smith MA, Perry G, Richey PL, Sayre LM, Anderson VE, Beal MF, Kowall N (1996) Oxidative damage in Alzheimer's. Nature 382:120–121
Smith MA, Harris PLR, Sayre LM, Beckman JS, Perry G (1997) Widespread peroxynitrite-mediated damage in Alzheimer's disease. J Neurosci 17:2653–2657
Sternberger LA (ed) (1986) Immunocytochemistry. Wiley, New York
Tabaton M, Cammarata S, Mancardi GL, Cordone G, Perry G, Loeb C (1991) Abnormal tau-reactive filaments in olfactory mucosa in biopsy specimens of patients with probable Alzheimer's disease. Neurology 41:391–394
Trojanowski JQ, Newman PD, Hill WD, Lee VM (1991) Human olfactory epithelium in normal aging, Alzheimer's disease, and other neurodegenerative disorders. J Comp Neurol 310:365–376
Wolozin BL, Sunderland T, Zheng BB, Resau J, Dufy B, Barker J, Swerdlow R, Coon H (1992) Continuous culture of neuronal cells from adult human olfactory epithelium. J Mol Neurosci 3:137–146
Zhu X, Rottkamp CA, Raina AK, Brewer GJ, Ghanbari HA, Boux H, Smith MA (2000) Neuronal CDK7 in hippocampus is related to aging and Alzheimer disease. Neurobiol Aging 21:807–813
Acknowledgements
This work was supported by the National Institutes of Health, the Alzheimer's Association, and Panacea Pharmaceuticals. Mark A. Smith and George Perry are compensated consultants and own equity in Panacea Pharmaceuticals.
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Perry, G., Castellani, R.J., Smith, M.A. et al. Oxidative damage in the olfactory system in Alzheimer's disease. Acta Neuropathol 106, 552–556 (2003). https://doi.org/10.1007/s00401-003-0761-7
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DOI: https://doi.org/10.1007/s00401-003-0761-7