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Cited by 611Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchAntioxidant Activity and Oxidative Stress

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Involvement of Oxidative Stress in Alzheimer Disease

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Nunomura, Akihiko, Castellani, Rudy J., Zhu, Xiongwei, Moreira, Paula I., Perry, George, Smith, Mark A.·2006·Journal of Neuropathology and Experimental Neurology
DOI 10.1097/01.jnen.0000228136.58062.bf
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Abstract

Genetic and lifestyle-related risk factors for Alzheimer disease (AD) are associated with an increase in oxidative stress, suggesting that oxidative stress is involved at an early stage of the pathologic cascade. Moreover, oxidative stress is mechanistically and chronologically associated with other key features of AD, namely, metabolic, mitochondrial, metal, and cell-cycle abnormalities. Contrary to the commonly held notion that pathologic hallmarks of AD signify etiology, several lines of evidence now indicate that aggregation of amyloid-beta and tau is a compensatory response to underlying oxidative stress. Therefore, removal of proteinaceous accumulations may treat the epiphenomenon rather than the disease and may actually enhance oxidative damage. Although some antioxidants have been shown to reduce the incidence of AD, the magnitude of the effect may be modified by individual factors such as genetic predisposition (e.g. apolipoprotein E genotype) and habitual behaviors. Because caloric restriction, exercise, and intellectual activity have been experimentally shown to promote neuronal survival through enhancement of endogenous antioxidant defenses, a combination of dietary regimen of low total calorie and rich antioxidant nutrients and maintaining physical and intellectual activities may ultimately prove to be one of the most efficacious strategies for AD prevention.

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  • ROS, which are considered markers of oxidative stress, are generated in the cytoplasm of neurons and can cause damage to key cellular components, including DNA, proteins, and lipids, leading to neuronal dysfunction and death.

    “It has been proposed that ROS, which are considered markers of oxidative stress, are generated in the cytoplasm of neurons and can cause damage to key cellular components, including DNA, proteins, and lipids, leading to neuronal dysfunction and death (56, 59, 60).”

    From Molecular Basis for Increased Risk for Late-onset Alzheimer Disease Due to the Naturally Occurring L28P Mutation in Apolipoprotein E4 (2014) · cites this paper as [56]

    The Introduction reports oxidation of nucleic acids, proteins, and lipids in early Alzheimer disease, and the Conclusion describes a model in which increased oxidative stress causes neuronal death. Our copy does not establish that ROS are generated in neuronal cytoplasm or identify ROS themselves as markers of oxidative stress; its cytoplasmic observation concerns an oxidized nucleoside, 8OHG. (LLM, conf=0.85)

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  • Oxidative stress is one of the earliest events in Alzheimer disease and plays important roles in the onset and progression of the disease, and this stress has been suggested to be chronic in neurons.

    “Oxidative stress has also been proposed to be one of the earliest events in AD that plays important roles in the onset and progression of the disease.”

    From Molecular Basis for Increased Risk for Late-onset Alzheimer Disease Due to the Naturally Occurring L28P Mutation in Apolipoprotein E4 (2014) · cites this paper as [56]

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Metadata

Authors
Nunomura, A., Castellani, R. J., Zhu, X., Moreira, P. I., Perry, G., & Smith, M. A.
Affiliations
  • Asahikawa Medical University (JP)
  • University of Maryland, Baltimore (US)
  • Case Western Reserve University (US)
  • Centro de Neurociências e Biologia Celular (PT)
Corresponding author
Smith, Mark A.
ORCID
Venue
Journal of Neuropathology and Experimental Neurology
Publisher
Oxford University Press (OUP)
Published
2006-07
Volume
65
Issue
7
Pages
631-641
ISSN
0022-3069 (ISSN-L)
DOI
10.1097/01.jnen.0000228136.58062.bf
OpenAlex
W2078089123
Cited by
611
References
25
Citations by year
2026: 5 · 2025: 24 · 2024: 26 · 2023: 26 · 2022: 34 · 2021: 29 · 2020: 36 · 2019: 21 · 2018: 26 · 2017: 32 · 2016: 42 · 2015: 39 · 2014: 31 · 2013: 35 · 2012: 37
FWCI
4.16
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuropathology & Experimental Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • Institutional Repositories DataBase (IRDB) (submittedVersion)
  • Asahikawa Medical University Collection and Research (Asahikawa Medical University) (submittedVersion)
Funders
  • Alzheimer's Association
  • Philip Morris International
  • National Institutes of Health
  • Japan Society for the Promotion of Science
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
Keywords
Alzheimer's disease, oxidative stress, amyloid-beta aggregation, tau aggregation, antioxidants, apolipoprotein E, caloric restriction, physical activity, intellectual activity, mitochondrial dysfunction, metal metabolism, cell cycle, neurodegeneration prevention
MeSH terms
Alzheimer Disease, Animals, Antioxidants, Disease Models, Animal, Humans, Neurons, Risk Factors, Vitamin E, Cell Death, Oxidative Stress, Disease Progression, Neuroprotective Agents, Genetic Predisposition to Disease, Risk Reduction Behavior, Plaque, Amyloid

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