title: Oxidative damage is the earliest event in Alzheimer disease.
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.
authors.affiliation: Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: A
authors.initials: A
authors.lastname: Nunomura
authors.forename: G
authors.initials: G
authors.lastname: Perry
authors.forename: G
authors.initials: G
authors.lastname: Aliev
authors.forename: K
authors.initials: K
authors.lastname: Hirai
authors.forename: A
authors.initials: A
authors.lastname: Takeda
authors.forename: E K
authors.initials: EK
authors.lastname: Balraj
authors.forename: P K
authors.initials: PK
authors.lastname: Jones
authors.forename: H
authors.initials: H
authors.lastname: Ghanbari
authors.forename: T
authors.initials: T
authors.lastname: Wataya
authors.forename: S
authors.initials: S
authors.lastname: Shimohama
authors.forename: S
authors.initials: S
authors.lastname: Chiba
authors.forename: C S
authors.initials: CS
authors.lastname: Atwood
authors.forename: R B
authors.initials: RB
authors.lastname: Petersen
authors.forename: M A
authors.initials: MA
authors.lastname: Smith
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics; D001921:Brain / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D005260:Female; D005838:Genotype; D006151:Guanosine / Q000031:analogs & derivatives / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D006151:Guanosine; C002744:3-nitrotyrosine; C046215:8-hydroxyguanosine; D014443:Tyrosine