Abstract
Brain aging is one of the most complex issues confronting researchers in neuroscience today. Nevertheless, research on the molecular biology of neurodegenerative disorders, particularly Alzheimer disease, has provided enormous progress in understanding the mechanisms that ultimately lead to the neuronal and glial malfunctions that ultimately damage neurons resulting in death. In this regard, one of the most compelling theories providing a basis for understanding aging and neurodegeneration posits oxidative stress, which results from an accumulation of “free radicals” in the cell that originates from the intense oxidative metabolism in the central nervous system and the diminished antioxidant defenses, as a major contributor. Here we review evidence demonstrating a robust relationship—epidemiological-clinical, molecular-neurobiological, and pathogenetic—between brain senility, mild cognitive impairment, and Alzheimer disease (as well as other neurodegenerative conditions) that places oxidative stress at a pivotal point in these three neurophysiologic and neuropathologic processes. These observations suggest that the three conditions are steps in the progressive decline in cognitive function. First, we focus on classical, clinical, and psychiatric observations of the cognitive ability of elderly people, from normal functioning to declines associated with aging, and then move to mild and severe pathological impairment, with continually worsening clinical and neuropsychiatric status. We show that the term “senile dementia”, today removed from the nosological categories, is in fact representative of the clinical observations of progressive age-related brain deterioration. Second, we address oxidative stress and describe the new neurochemical and neuropathological theories of disease pathogenesis, that implicate oxidative stress as the earliest process in brain aging and neurodegeneration in Alzheimer disease. Moreover, we discuss the evidence that amyloid-β, senile plaques, and neurofibrillary tangles may comprise a compensatory defense mechanism against oxidative stress. In addition, the oxidative stress-amyloid-β “cascade” that develops during Alzheimer disease is also described, in which amyloid formation in the brain further exposes neurons to oxidative stress, eliciting a full neurodegenerative response. Finally, we explore how current treatments of Alzheimer disease, such as acetylcholinesterase inhibitors and non-specific glutamate receptor inhibitors/antagonists, may benefit from the inclusion of antioxidants or metabolic agents that target brain aging, mild cognitive impairment, Alzheimer disease, and other neurodegenerative diseases.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Abbreviations
- AD:
-
Alzheimer disease
- AβPP:
-
amyloid-β protein precursor
- CNS:
-
central nervous system
- FAD:
-
familial Alzheimer disease
- 8OHG:
-
8-hydroxyguanosine
- •OH:
-
hydroxyl radical
- LOAD:
-
late onset AD
- MCI:
-
mild cognitive impairment
- mtDNA:
-
mitochondrial DNA
- PUFA:
-
polyunsaturated fatty acids
- PET:
-
positron emission tomography
- RNS:
-
reactive nitrogen species
- ROS:
-
reactive oxygen species
References
Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol 1956; 11:298–300
Perez-Campo R, Lopez-Torres M, Cadenas S, Rojas C, Barja G. The rate of free radical production as a determinant of the rate of aging: evidence from the comparative approach. J Comp Physiol B 1998; 168:149–158
Jaruga P, Dizdaroglu M. Repair of products of oxidative DNA base damage in human cells. Nucleic Acids Res 1996; 24:1389–1394
Stone HB, Coleman CN, Anscher MS, McBride WH. Effects of radiation on normal tissue: consequences and mechanisms. Lancet Oncol 2003; 4:529–536
Markesbery WR, Montine TJ, Lovell MA. Oxidative alterations in neurodegenerative diseases. In: Mattson MP (eds) Pathogenesis of Neurodegenerative Disorders. Humana Press Inc., Totowa, NJ, 2001; pp. 21–52
Perry G, Nunomura A, Raina AK, et al. A metabolic basis for Alzheimer disease. Neurochem Res 2003; 28:1549–1552
Honda K, Smith MA, Zhu X, et al. Ribosomal RNA in Alzheimer disease is oxidized by bound redox-active iron. J Biol Chem 2005; 280:20978–20986
Berg D. Redox imbalance: in the triad of genetic disturbances and mitochondrial dysfunction in Parkinson’s disease. In: Qureshi GA, Parvez SH (eds) Oxidative Stress and Neurodegenerative Disorders. Elsevier B.V., Amsterdam, 2007; pp. 183–200
Daffner KR, Scinto LFM. Early diagnosis of Alzheimer’s disease: an introduction. In: Daffner KR, Scinto LFM (eds) Early Diagnosis of Alzheimer’s Disease. Humana Press, Inc., Totowa, NJ, 2000; pp. 1–28
American Psychiatric Association. The Diagnostic and Statistical Manual of Mental Disorders, text revision (DSM-IV-TR), 4th edn. American Psychiatric Association, Washington, DC; 2004
Morris JC, Heyman A, Mohs RC, et al. The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer’s disease. Neurology 1989; 39:1159–1165
Bachman DL, Wolf PA, Linn RT, et al. Incidence of dementia and probable Alzheimer’s disease in a general population: the Framingham Study. Neurology 1993; 43:515–519
Paykel ES, Brayne C, Huppert FA, et al. Incidence of dementia in a population older than 75 years in the United Kingdom. Arch Gen Psychiatry 1994; 51:325–332
Myers GC. World statistical trend prospects. In: Copeland JRM, Abou-Saleh MT Blazer DG (eds) Principles and Practice of Geriatric Psychiatry. John Wiley & Sons, Ltd., New York, 2002; pp. 87–121
United Nations. World Population Prospects: The 2008 Revision. 2008
Evans DA, Funkenstein HH, Albert MS, et al. Prevalence of Alzheimer’s disease in a community population of older persons. Higher than previously reported. JAMA 1989; 262:2551–2556
Ritchie K, Kildea D. Is senile dementia “age-related” or “ageing-related”?—evidence from meta-analysis of dementia prevalence in the oldest old. Lancet 1995; 346:931–934
Small GW, Rabins PV, Barry PP, et al. Diagnosis and treatment of Alzheimer disease and related disorders. Consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer’s Association, and the American Geriatrics Society. JAMA 1997; 278:1363–1371
Jorm AF. The Epidemiology of Alzheimer’s Disease and Related Disorders. Chapman & Hall, London; 1990
Vijg J. Aging of the Genome: the Dual Role of the DNA in Life and Death. Oxford University Press, Oxford; 2007
Watson JD, Baker TA, Bell SP, et al. Molecular Biology of the Gene, 6th edn. Pearson Education Inc., UK; 2008
Lee H-C, Wei Y-H. Mitochondrial DNA mutation, oxidative stress, and alteration of gene expression in human aging. In: Berdainer CD (eds) Mitochondria in Health and Disease. Taylor & Francis, Boca Raton, 2005; pp. 319–362
Lindahl T. Instability and decay of the primary structure of DNA. Nature 1993; 362:709–715
Adelman R, Saul RL, Ames BN. Oxidative damage to DNA: relation to species metabolic rate and life span. Proc Natl Acad Sci USA 1988; 85:2706–2708
Barja G. Free radicals and aging. Trends Neurosci 2004; 27:595–600
Shoffner JM. Oxidative phosphorylation disease: diagnosis and pathogenesis. In: Berdainer CD (eds) Mitochondria in Health and Disease. Taylor & Francis, Boca Raton, 2005; pp. 247–300
Tengan CH, Gabbai AA, Shanske S, Zeviani M, Moraes CT. Oxidative phosphorylation dysfunction does not increase the rate of accumulation of age-related mtDNA deletions in skeletal muscle. Mutat Res 1997; 379:1–11
Hirai K, Aliev G, Nunomura A, et al. Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci 2001; 21:3017–3023
Blass JP, Sheu RK, Gibson GE. Inherent abnormalities in energy metabolism in Alzheimer disease. Interaction with cerebrovascular compromise. Ann NY Acad Sci 2000; 903:204–221
Gabuzda D, Busciglio J, Chen LB, Matsudaira P, Yankner BA. Inhibition of energy metabolism alters the processing of amyloid precursor protein and induces a potentially amyloidogenic derivative. J Biol Chem 1994; 269:13623–13628
Moreira PI, Nunomura A, Honda K, et al. The key role of oxidative stress in Alzheimer’s disease. In: Qureshi GA, Parvez SH (eds) Oxidative Stress and Neurodegenerative Disorders. Elsevier B.V., Amsterdam, 2007; pp. 267–281
Zhu X, Rottkamp CA, Boux H, et al. Activation of p38 kinase links tau phosphorylation, oxidative stress, and cell cycle-related events in Alzheimer disease. J Neuropathol Exp Neurol 2000; 59:880–888
Tanaka M, Kovalenko SA, Gong JS, et al. Accumulation of deletions and point mutations in mitochondrial genome in degenerative diseases. Ann NY Acad Sci 1996; 786:102–111
Wei YH. Oxidative stress and mitochondrial DNA mutations in human aging. Proc Soc Exp Biol Med 1998; 217:53–63
Wilson DM 3rd, Bohr VA, McKinnon PJ. DNA damage, DNA repair, ageing and age-related disease. Mech Ageing Dev 2008; 129:349–352
Linnane AW, Marzuki S, Ozawa T, Tanaka M. Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet 1989; 1:642–645
Raha S, Robinson BH. Mitochondria, oxygen free radicals, disease and ageing. Trends Biochem Sci 2000; 25:502–508
Druzhyna NM, Wilson GL, LeDoux SP. Mitochondrial DNA repair in aging and disease. Mech Ageing Dev 2008; 129:383–390
Isobe K, Ito S, Hosaka H, et al. Nuclear-recessive mutations of factors involved in mitochondrial translation are responsible for age-related respiration deficiency of human skin fibroblasts. J Biol Chem 1998; 273:4601–4606
Nunomura A, Perry G, Aliev G, et al. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 2001; 60:759–767
Akbari M, Krokan HE. Cytotoxicity and mutagenicity of endogenous DNA base lesions as potential cause of human aging. Mech Ageing Dev 2008; 129:353–365
Rottkamp CA, Raina AK, Zhu X, et al. Redox-active iron mediates amyloid-beta toxicity. Free Radic Biol Med 2001; 30:447–450
Gouras GK, Tsai J, Naslund J, et al. Intraneuronal Abeta42 accumulation in human brain. Am J Pathol 2000; 156:15–20
Sayre LM, Perry G, Harris PL, et al. In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer’s disease: a central role for bound transition metals. J Neurochem 2000; 74:270–279
Blass JP, Gibson GE. Cerebrometabolic aspects of delirium in relationship to dementia. Dement Geriatr Cogn Disord 1999; 10:335–338
Azari NP, Pettigrew KD, Schapiro MB, et al. Early detection of Alzheimer’s disease: a statistical approach using positron emission tomographic data. J Cereb Blood Flow Metab 1993; 13:438–447
Pettegrew JW, Panchalingam K, Klunk WE, McClure RJ, Muenz LR. Alterations of cerebral metabolism in probable Alzheimer’s disease: a preliminary study. Neurobiol Aging 1994; 15:117–132
Reiman EM, Chen K, Alexander GE, et al. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer’s dementia. Proc Natl Acad Sci USA 2004; 101:284–289
Hoyer S. Risk factors for Alzheimer’s disease during aging. Impacts of glucose/energy metabolism. J Neural Transm Suppl 1998; 54:187–194
Atwood CS, Obrenovich ME, Liu T, et al. Amyloid-beta: a chameleon walking in two worlds: a review of the trophic and toxic properties of amyloid-beta. Brain Res Brain Res Rev 2003; 43:1–16
Nunomura A, Perry G, Pappolla MA, et al. Neuronal oxidative stress precedes amyloid-beta deposition in Down syndrome. J Neuropathol Exp Neurol 2000; 59:1011–1017
Nunomura A, Perry G, Pappolla MA, et al. RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer’s disease. J Neurosci 1999; 19:1959–1964
Nunomura A, Perry G, Hirai K, et al. Neuronal RNA oxidation in Alzheimer’s disease and Down’s syndrome. Ann NY Acad Sci 1999; 893:362–364
Kontush A. Amyloid-beta: an antioxidant that becomes a pro-oxidant and critically contributes to Alzheimer’s disease. Free Radic Biol Med 2001; 31:1120–1131
Cappai R, Needham BE, Ciccotosto GD. The function of the amyloid precursor protein family. In: Collin JB, David HS (eds) Abeta Peptide and Alzheimer’s Disease: Celebrating a Century of Research. Springer, London, 2007; pp. 37–51
Buee L, Bussiere T, Buee-Scherrer V, Delacourte A, Hof PR. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev 2000; 33:95–130
Sontag E, Nunbhakdi-Craig V, Lee G, et al. Molecular interactions among protein phosphatase 2A, tau, and microtubules. Implications for the regulation of tau phosphorylation and the development of tauopathies. J Biol Chem 1999; 274:25490–25498
Morsch R, Simon W, Coleman PD. Neurons may live for decades with neurofibrillary tangles. J Neuropathol Exp Neurol 1999; 58:188–197
Scheffler IE. Mitochondria, 2nd edn. John Wiley & Sons, Inc., Hoboken, NJ; 2008
Mecocci P, MacGarvey U, Beal MF. Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease. Ann Neurol 1994; 36:747–751
Wallace DC, Singh G, Lott MT, et al. Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 1988; 242:1427–1430
Holt IJ, Harding AE, Morgan-Hughes JA. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 1988; 331:717–719
Beal MF. Aging, energy, and oxidative stress in neurodegenerative diseases. Ann Neurol 1995; 38:357–366
Sapolsky RM. Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatry 2000; 57:925–935
McEwen BS. Stress and hippocampal plasticity. Annu Rev Neurosci 1999; 22:105–122
Wong ML, Licinio J. Research and treatment approaches to depression. Nat Rev Neurosci 2001; 2:343–351
Kendler KS, Karkowski LM, Prescott CA. Causal relationship between stressful life events and the onset of major depression. Am J Psychiatry 1999; 156:837–841
Sapolsky RM. The possibility of neurotoxicity in the hippocampus in major depression: a primer on neuron death. Biol Psychiatry 2000; 48:755–765
Horner HC, Packan DR, Sapolsky RM. Glucocorticoids inhibit glucose transport in cultured hippocampal neurons and glia. Neuroendocrinology 1990; 52:57–64
Tombaugh GC, Sapolsky RM. Evolving concepts about the role of acidosis in ischemic neuropathology. J Neurochem 1993; 61:793–803
Del Rio J, Frencilla D. Glutamate and depression. In: Schmidt WJ, Reith MEA (eds) Dopamine and Glutamate in Psychiatric Disorders. Humana Press, Totowa, NJ, 2005; pp. 215–234
Smith MA, Makino S, Kvetnansky R, Post RM. Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci 1995;15:1768–1777
Smith MA, Rodrigues R. The twin frontiers of depression and Alzheimer’s disease. Front Neurosci 2009; 3:236–237
Bonni A, Brunet A, West AE, et al. Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 1999; 286:1358–1362
Geerlings MI, den Heijer T, Koudstaal PJ, Hofman A, Breteler MM. History of depression, depressive symptoms, and medial temporal lobe atrophy and the risk of Alzheimer disease. Neurology 2008; 70:1258–1264
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2010 Springer Science+Business Media B.V.
About this chapter
Cite this chapter
Rodrigues, R. et al. (2010). Oxidative Stress and Neurodegeneration: An Inevitable Consequence of Aging? Implications for Therapy. In: Ritsner, M. (eds) Brain Protection in Schizophrenia, Mood and Cognitive Disorders. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-8553-5_10
Download citation
DOI: https://doi.org/10.1007/978-90-481-8553-5_10
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-90-481-8552-8
Online ISBN: 978-90-481-8553-5
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)