Abstract
Recent advances have shown oxidative damage as one of the hallmark characteristics in neurons in Alzheimer’s Disease (AD). Importantly, such damage is present at the very earliest stages of disease, including mild cognitive impairment, and persists throughout the course of the disease. Therefore, oxidative imbalance is likely important not only as an initiator of disease but may also contribute in propagating the disease process. One aspect of critical importance is developing treatments that target the source rather than the “collateral damage,” but of course this requires knowledge of the source. This review highlights the role of oxidative stress in AD with the aim of critically evaluating the role of oxidative stress as a cause or effect in the development of this disease. In doing so, we consider the sources of reactive oxidative species and their role in AD as well as how oxidative responses intertwine with the pathological hallmarks of the disease.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Bendlin, B.B., et al. (2010) Midlife predictors of Alzheimer’s disease. Maturitas 65(2):131–137
Salminen, A., et al. (2009) ER stress in Alzheimer’s disease: a novel neuronal trigger for inflammation and Alzheimer’s pathology. Journal of Neuroinflammation 6(1): 41
Beyer, N., et al. (2009) ZnT3 mRNA levels are reduced in Alzheimer’s disease post-mortem brain. Molecular Neurodegeneration 4(1): 53
Zhu, H.L., et al. (2009) Quantitative characterization of heparin binding to Tau protein: Implication for inducer mediated Tau filament formation. Journal of Biological Chemistry 285(6):3592–3599
Nicolia, V., et al. (2010) B vitamin deficiency promotes tau phosphorylation through regulation of gsk3β and pp2A. Journal of Alzheimer’s Disease 19(3):895–907
Isobe, C., T. Abe, and Y. Terayama (2009) Increase in the oxidized/total coenzyme Q-10 ratio in the cerebrospinal fluid of Alzheimer’s disease patients. Dement Geriatr Cogn Disord 28(5):449–454
Andersen, J.K. (2004) Oxidative stress in neurodegeneration: cause or consequence? Nat Med 10 Suppl: S18–25
Sayre, L.M., M.A. Smith, and G. Perry (2001) Chemistry and biochemistry of oxidative stress in neurodegenerative disease. Curr Med Chem 8(7): 721–38
Sharma, S., et al. (2009) Dietary curcumin supplementation counteracts reduction in levels of molecules involved in energy homeostasis after brain trauma. Neuroscience 161(4):1037–1044
Roberts, G.W., et al. (1991) [beta]A4 amyloid protein deposition in brain after head trauma. The Lancet 338(8780):1422–1423
Pratico, D., et al. (2001) Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J Neurosci 21(12): 4183–4187
Nunomura, A., et al. (2010) Intraneuronal amyloid beta accumulation and oxidative damage to nucleic acids in Alzheimer’s Disease. Neurobiol Dis 37(3):731–737
Rottkamp, C.A., et al. (2002) The state versus amyloid-beta: the trial of the most wanted criminal in Alzheimer’s Disease. Peptides 23(7): 1333–1341
Zou, K., et al. (2002) A novel function of monomeric amyloid beta-protein serving as an antioxidant molecule against metal-induced oxidative damage. J Neurosci 22(12): 4833–4841
Meloy, S. (2007) Neurally augmented sexual function. Acta Neurochir Suppl 97(1):359-63
Gustaw-Rothenberg, K., et al. (2010) Biomarkers in Alzheimer’s disease: past, present and future. Biomark Med 4(1):15–26
Anouar, E., et al. (2009) Free radical scavenging properties of guaiacol oligomers: a combined experimental and quantum study of the guaiacyl-moiety role. J Phys Chem A 113(50):13881–13891
Kirkitadze, M.D., G. Bitan, and D.B. Teplow (2002) Paradigm shifts in Alzheimer’s disease and other neurodegenerative disorders: the emerging role of oligomeric assemblies. J Neurosci Res 69(5): p. 567–577
Gotz, J., et al. (2004) Amyloid-induced neurofibrillary tangle formation in Alzheimer’s disease: insight from transgenic mouse and tissue-culture models. Int J Dev Neurosci 22(7):453–465
German, D.C. and A.J. Eisch, (2004) Mouse models of Alzheimer’s disease: insight into treatment. Rev Neurosci 15(5):353–369
Bentahir, M., et al. (2006) Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J Neurochem 96(3):732–742
Kumar-Singh, S., et al. (2006) Mean age-of-onset of familial Alzheimer’s Disease caused by presenilin mutations correlates with both increased Abeta42 and decreased Abeta40. Hum Mutat 27(7): 686–695
Shioi, J., et al. (2007) FAD mutants unable to increase neurotoxic Abeta 42 suggest that mutation effects on neurodegeneration may be independent of effects on Abeta. J Neurochem 101(3):674–681
Lee, H.G., et al. (2007) Amyloid-beta in Alzheimer’s Disease: the null versus the alternate hypotheses. J Pharmacol Exp Ther 321(3):823–829
Walsh, D.M. and D.J. Selkoe (2007) A beta oligomers - a decade of discovery. J Neurochem 101(5): p. 1172–1184
Catalano, S.M., et al. (2006) The role of amyloid-beta derived diffusible ligands (ADDLs) in Alzheimer’s disease. Curr Top Med Chem 6(6):597–608
Glabe, C.G. and R. Kayed (2006) Common structure and toxic function of amyloid oligomers implies a common mechanism of pathogenesis. Neurology 66(2 Suppl 1):S74–S78
Watson, D. et al. (2005) Physicochemical characteristics of soluble oligomeric Abeta and their pathologic role in Alzheimer’s disease. Neurol Res 27(8):869–881
Selkoe, D.J. (2005) Defining molecular targets to prevent Alzheimer’s Disease. Arch Neurol 62(2):192–195
King, M.E. (2005) Can tau filaments be both physiologically beneficial and toxic? Biochim Biophys Acta 1739(2-3):260–267
Hanger, D.P., et al. (1998) New phosphorylation sites identified in hyperphosphorylated tau (paired helical filament-tau) from Alzheimer’s disease brain using nanoelectrospray mass spectrometry. J Neurochem 71(6):2465–2476
Stoothoff, W.H. and Johnson G.V. (2005) Tau phosphorylation: physiological and pathological consequences. Biochim Biophys Acta 1739(2-3):280–297
Iqbal, K., et al. (1994) Alzheimer paired helical filaments. Restoration of the biological activity by dephosphorylation. FEBS Lett 349(1):104–108
Iqbal, K., et al. (2005) Tau pathology in Alzheimer’s Disease and other tauopathies. Biochim Biophys Acta 1739(2-3):198–210
Keck, S., et al. (2003) Proteasome inhibition by paired helical filament-tau in brains of patients with Alzheimer’s disease. J Neurochem 85(1):115–122
Cras, P., et al. (1995) Extracellular neurofibrillary tangles reflect neuronal loss and provide further evidence of extensive protein cross-linking in Alzheimer’s Disease. Acta Neuropathol 89(4):291–295
Smith, M.A. (1998) Alzheimer’s Disease. Int Rev Neurobiol 42:1–54
Castellani, R.J., et al. (2007) Neuropathology and treatment of Alzheimer’s Disease: did we lose the forest for the trees? Expert Rev Neurother 7(5):473–485
Martin, M.A., et al. (2009) Protection of human HepG2 cells against oxidative stress by the flavonoid epicatechin. Phytother Res 24(4):503–509
Esmaeili, M.A. and Sonboli, A. (2009) Antioxidant, free radical scavenging activities of Salvia brachyantha and its protective effect against oxidative cardiac cell injury. Food Chem Toxicol 48(3):846–53
Kachadourian, R., et al. (2009) Casiopeina IIgly-induced oxidative stress and mitochondrial dysfunction in human lung cancer A549 and H157 cells. Toxicology 268(3):176–83
Norberg, E., et al. (2009) Oxidative modification sensitizes mitochondrial apoptosis-inducing factor to calpain-mediated processing. Free Radic Biol Med 48(6):791–797
Sesti, F., Liu, S., and Cai, S.Q. (2009) Oxidation of potassium channels by ROS: a general mechanism of aging and neurodegeneration? Trends Cell Biol 20(1):45–51
Sayre, L.M., Perry, G. and Smith, M.A. (1999) In situ methods for detection and localization of markers of oxidative stress: application in neurodegenerative disorders. Methods Enzymol 309:133–152
Nunomura, A., et al. (1999) RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer’s disease. J Neurosci, 1999. 19(6):1959–1964
Nunomura, A., et al. (2001) Oxidative damage is the earliest event in Alzheimer’s Disease.J Neuropathol Exp Neurol 60(8):759–767
Gabbita, S.P., Lovell, M.A., and Markesbery, W.R. (1998) Increased nuclear DNA oxidation in the brain in Alzheimer’s disease. J Neurochem 71(5): p. 2034–2040
Lovell, M.A., Gabbita, S.P., and Markesbery, W.R. (1999), Increased DNA oxidation and decreased levels of repair products in Alzheimer’s disease ventricular CSF. J Neurochem 72(2): 771–776
Smith, M.A., et al. (1997) Widespread peroxynitrite-mediated damage in Alzheimer’s disease. J Neurosci 17(8):2653–2657
Smith, M.A., et al. (1996) Oxidative damage in Alzheimer’s. Nature 382(6587):120–121
Hensley, K., et al. (1998) Electrochemical analysis of protein nitrotyrosine and dityrosine in the Alzheimer brain indicates region-specific accumulation. J Neurosci 18(20):8126–8132
Montine, K.S., et al. (2004) Isoprostanes and related products of lipid peroxidation in neurodegenerative diseases. Chem Phys Lipids 128(1-2):117–124
Montine, K.S., et al. (1998) Distribution of reducible 4-hydroxynonenal adduct immunoreactivity in Alzheimer’s Disease is associated with APOE genotype. J Neuropathol Exp Neurol 57(5):415–425
Montine, K.S., et al. (1997) Immunohistochemical detection of 4-hydroxy-2-nonenal adducts in Alzheimer’s disease is associated with inheritance of APOE4. Am J Pathol 150(2):437–443
Sayre, L.M., et al. (1997) 4-Hydroxynonenal-derived advanced lipid peroxidation end products are increased in Alzheimer’s disease. J Neurochem 68(5):2092–2097
Ando, Y., et al. (1998) Histochemical detection of 4-hydroxynonenal protein in Alzheimer amyloid. J Neurol Sci 156(2):172–176
Keller, J.N., et al.., (2005) Evidence of increased oxidative damage in subjects with mild cognitive impairment. Neurology 64(7):1152–1156
Calingasan, N.Y., Uchida, K., and Gibson, G.E. (1999) Protein-bound acrolein: a novel marker of oxidative stress in Alzheimer’s disease. J Neurochem 72(2):751–756
Smith, M.A., et al. (1994) Advanced Maillard reaction end products are associated with Alzheimer’s Disease pathology. Proc Natl Acad Sci USA 91(12): p. 5710–5714
Vitek, M.P., et al. (1994) Advanced glycation end products contribute to amyloidosis in Alzheimer’s Disease. Proc Natl Acad Sci USA, 91(11):4766–4770
Yan, S.D., et al. (1994) Glycated tau protein in Alzheimer’s Disease: a mechanism for induction of oxidant stress. Proc Natl Acad Sci USA, 91(16):7787–7791
Ledesma, M.D., et al. (1994) Analysis of microtubule-associated protein tau glycation in paired helical filaments. J Biol Chem 269(34):21614–21619
Castellani, R.J., et al. (2001) Active glycation in neurofibrillary pathology of Alzheimer’s Disease: N(epsilon)-(carboxymethyl) lysine and hexitol-lysine. Free Radic Biol Med 31(2):175–180
Perry, G., et al. (2000) How important is oxidative damage? Lessons from Alzheimer’s disease. Free Radic Biol Med 28(5): 831–834
Ko, L.W., et al. (1999) An immunochemical study on tau glycation in paired helical filaments. Brain Res 830(2): 301–313
Liu, Q., et al. (2005) Alzheimer-specific epitopes of tau represent lipid peroxidation-induced conformations. Free Radic Biol Med 38(6):746–754
Sullivan, P.G. and Brown M.R. (2005) Mitochondrial aging and dysfunction in Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry 29(3):407–410
Castellani, R.J., et al. (2004) Contribution of redox-active iron and copper to oxidative damage in Alzheimer’s Disease. Ageing Res Rev 3(3): 319–326
Smith, M.A., et al. (1994) Heme oxygenase-1 is associated with the neurofibrillary pathology of Alzheimer’s disease. Am J Pathol 145(1): 42–47
Premkumar, D.R., et al. (1995) Induction of heme oxygenase-1 mRNA and protein in neocortex and cerebral vessels in Alzheimer’s disease. J Neurochem 65(3):1399–1402
Schipper, H.M., Cisse, S., and Stopa, E.G. (1995) Expression of heme oxygenase-1 in the senescent and Alzheimer-diseased brain. Ann Neurol 37(6):758–768
Bonilla, E., et al. (1999) Mitochondrial involvement in Alzheimer’s disease. Biochim Biophys Acta 1410(2):171–182
Aliev, G., et al. (2002) Atherosclerotic lesions and mitochondria DNA deletions in brain microvessels as a central target for the development of human AD and AD-like pathology in aged transgenic mice. Ann N Y Acad Sci 977:45–64
Pappolla, M.A., et al. (1992) Immunohistochemical evidence of oxidative [corrected] stress in Alzheimer’s disease. Am J Pathol 140(3):621–628
De Leo, M.E., et al. (1998) Oxidative stress and overexpression of manganese superoxide dismutase in patients with Alzheimer’s disease. Neurosci Lett 250(3):173–6
Marcus, D.L., et al. (1998) Increased peroxidation and reduced antioxidant enzyme activity in Alzheimer’s disease. Exp Neurol 150(1):40–44
Perry, G., et al. (2002) Comparative biology and pathology of oxidative stress in Alzheimer and other neurodegenerative diseases: beyond damage and response. Comp Biochem Physiol C Toxicol Pharmacol 133(4):507–513
Zhu, X., et al. (2004) Oxidative stress signalling in Alzheimer’s disease. Brain Res 1000(1-2):32–39
Kurz, A. and Perneczky, R. (2009) Neurobiology of cognitive disorders. Curr Opin Psychiatry 22(6): 546–551
Sayre, L.M., et al. (2000) In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer’s disease: a central role for bound transition metals. J Neurochem 74(1):270–279
Nunomura, A., et al. (1999) Neuronal RNA oxidation in Alzheimer’s disease and Down’s syndrome. Ann N Y Acad Sci 893:362–364
Smith, M.A., et al. (2000) Metabolic, metallic, and mitotic sources of oxidative stress in Alzheimer’s Disease. Antioxid Redox Signal 2(3):413–420
Lynn, B.C., et al. (2010) Quantitative changes in the mitochondrial proteome from subjects with mild cognitive impairment, early stage, and late stage Alzheimer’s disease. J Alzheimers Dis 19(1):325–339
Spindler, M., Beal, M.F., and Henchcliffe, C. (2009) Coenzyme Q10 effects in neurodegenerative disease. Neuropsychiatr Dis Treat 5:597–610
Sayre, L.M., Perry, G., and Smith, M.A. (1999) Redox metals and neurodegenerative disease. Curr Opin Chem Biol 3(2): 220–225
Smith, M.A., et al. (2010) Increased iron and free radical generation in preclinical Alzheimer’s Disease and mild cognitive impairment. J Alzheimers Dis 19(1):363–372
Liu, G., et al. (2009) Metal chelators coupled with nanoparticles as potential therapeutic agents for Alzheimer’s disease. J Nanoneurosci 1(1): 42–55
Moreira, P.I., et al. (2008) Alzheimer’s Disease and the role of free radicals in the pathogenesis of the disease. CNS Neurol Disord Drug Targets 7(1):3–10
Mattson, M.P. (2006) Neuronal life-and-death signaling, apoptosis, and neurodegenerative disorders. Antioxid Redox Signal 8(11-12):1997–2006
Marlatt, M.W., et al. (2005) Therapeutic opportunities in Alzheimer’s Disease: one for all or all for one? Curr Med Chem 12(10): 1137–1147
Veurink, G., et al. (2003) Reduction of inclusion body pathology in ApoE-deficient mice fed a combination of antioxidants. Free Radic Biol Med 34(8):1070–1077
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2011 Springer Science+Business Media, LLC
About this chapter
Cite this chapter
Chang, J. et al. (2011). Oxidative Stress in Alzheimer’s Disease: A Critical Appraisal of the Causes and the Consequences. In: Basu, S., Wiklund, L. (eds) Studies on Experimental Models. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-956-7_9
Download citation
DOI: https://doi.org/10.1007/978-1-60761-956-7_9
Published:
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-60761-955-0
Online ISBN: 978-1-60761-956-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)