Cited by 1,885Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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Oxidative Damage Is the Earliest Event in Alzheimer Disease

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Nunomura, Akihiko, Perry, George, Aliev, Gjumrakch, Hirai, Keisuke, Takeda, Atsushi, Balraj, Elizabeth K., Jones, Paul K., Ghanbari, Hossein, Wataya, Takafumi, Shimohama, Shun, Chiba, Shigeru, Atwood, Craig S., Petersen, Robert B., Smith, Mark A.·2001·Journal of Neuropathology & Experimental Neurology

DOI 10.1093/jnen/60.8.759

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Abstract

Recently, we demonstrated a significant increase of an oxidized nucleoside derived from RNA, 8-hydroxyguanosine (8OHG), and an oxidized amino acid, nitrotyrosine in vulnerable neurons of patients with Alzheimer disease (AD). To determine whether oxidative damage is an early- or end-stage event in the process of neurodegeneration in AD, we investigated the relationship between neuronal 8OHG and nitrotyrosine and histological and clinical variables, i.e. amyloid-beta (A beta) plaques and neurofibrillary tangles (NFT), as well as duration of dementia and apolipoprotein E (ApoE) genotype. Our findings show that oxidative damage is quantitatively greatest early in the disease and reduces with disease progression. Surprisingly, we found that increases in A beta deposition are associated with decreased oxidative damage. These relationships are more significant in ApoE epsilon4 carriers. Moreover, neurons with NFT show a 40%-56% decrease in relative 8OHG levels compared with neurons free of NFT. Our observations indicate that increased oxidative damage is an early event in AD that decreases with disease progression and lesion formation. These findings suggest that AD is associated with compensatory changes that reduce damage from reactive oxygen.

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Authors: Nunomura, A., Perry, G., Aliev, G., Hirai, K., Takeda, A., Balraj, E. K., Jones, P. K., Ghanbari, H., Wataya, T., Shimohama, S., Chiba, S., Atwood, C. S., Petersen, R. B., & Smith, M. A.
Affiliations: Asahikawa Medical University (JP)
Case Western Reserve University (US)
Takeda (Japan) (JP)
Sensei Biotherapeutics (United States) (US)
Kyoto University (JP)
Corresponding author: Nunomura, Akihiko
ORCID: Nunomura, Akihiko
Perry, George
Aliev, Gjumrakch
Hirai, Keisuke
Takeda, Atsushi
Jones, Paul K.
Wataya, Takafumi
Shimohama, Shun
Chiba, Shigeru
Atwood, Craig S.
Petersen, Robert B.
Smith, Mark A.
Venue: Journal of Neuropathology & Experimental Neurology
Publisher: Oxford University Press (OUP)
Published: 2001-08
Volume: 60
Issue: 8
Pages: 759-767
ISSN: 0022-3069 (ISSN-L)
1554-6578
DOI: 10.1093/jnen/60.8.759
OpenAlex: W1542215809
Cited by: 1,885
References: 59
Citations by year: 2026: 46 · 2025: 31 · 2024: 52 · 2023: 61 · 2022: 80 · 2021: 98 · 2020: 86 · 2019: 82 · 2018: 69 · 2017: 73 · 2016: 70 · 2015: 83 · 2014: 86 · 2013: 86 · 2012: 104
FWCI: 33.08
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Neuropathology & Experimental Neurology (publishedVersion)
PubMed (publishedVersion)
Asahikawa Medical University Collection and Research (Asahikawa Medical University) (submittedVersion)
Institutional Repositories DataBase (IRDB) (submittedVersion)
Funders: Alzheimer's Association
National Institutes of Health (5r01ag009287-08, AG09287)
Japan Society for the Promotion of Science (12670918)
National Institute on Aging (AG-14249, R01AG014249, AG 09287)
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
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: Alzheimer's disease, oxidative damage, 8-hydroxyguanosine, nitrotyrosine, amyloid plaques, neurofibrillary tangles, APOE ε4, disease progression, neurodegeneration, reactive oxygen species, RNA oxidation
MeSH terms: Aged, Alzheimer Disease, Apolipoproteins E, Brain, Female, Genotype, Guanosine, Heterozygote, Humans, Male, Middle Aged, Neurons, Tyrosine, Amyloid beta-Peptides, Neurofibrillary Tangles, Oxidative Stress, Disease Progression, Plaque, Amyloid

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Oxidative Damage Is the Earliest Event in Alzheimer Disease

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