Oxidative Damage Is the Earliest Event in Alzheimer Disease

• Published in: Journal of neuropathology and experimental neurology Vol. 60; no. 8; pp. 759 - 767
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Association of Neuropathologists, Inc 01.08.2001; Lippincott Williams & Wilkins; Oxford University Press
• Subjects: Aged; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer Disease - psychology; Amyloid beta-Peptides - metabolism; Apolipoproteins E - genetics; Biological and medical sciences; Brain - metabolism; Brain - pathology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Progression; Female; Genotype; Guanosine - analogs & derivatives; Guanosine - metabolism; Heterozygote; Humans; Male; Medical sciences; Middle Aged; Neurofibrillary Tangles - pathology; Neurology; Neurons - metabolism; Neurons - pathology; Oxidative Stress; Plaque, Amyloid - metabolism; Plaque, Amyloid - pathology; Tyrosine - analogs & derivatives; Tyrosine - metabolism; Human; Oxidative stress; Nervous system diseases; Pathophysiology; Alzheimer disease; Immunocytochemistry; Neurofibrillary tangle; Cerebral disorder; Pathology; Autopsy; β Amyloid protein; Central nervous system disease; Degenerative disease
• ISSN: 0022-3069; 1554-6578
• DOI: 10.1093/jnen/60.8.759

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-β (Aβ) 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 Aβ deposition are associated with decreased oxidative damage. These relationships are more significant in ApoE ε4 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.