Intraneuronal amyloid beta accumulation and oxidative damage to nucleic acids in Alzheimer disease.
In an analysis of amyloid pathology in Alzheimer disease, we used an in situ approach to identify amyloid-beta (Abeta) accumulation and oxidative damage to nucleic acids in postmortem brain tissue of the hippocampal formation from subjects with Alzheimer disease. When carboxyl-terminal-specific antibodies directed against Abeta40 and Abeta42 were used for immunocytochemical analyses, Abeta42 was especially apparent within the neuronal cytoplasm, at sites not detected by the antibody specific to Abeta-oligomer. In comparison to the Abeta42-positive neurons, neurons bearing oxidative damage to nucleic acids were more widely distributed in the hippocampus. Comparative density measurements of the immunoreactivity revealed that levels of intraneuronal Abeta42 were inversely correlated with levels of intraneuronal 8-hydroxyguanosine, an oxidized nucleoside (r=- 0.61, p<0.02). Together with recent evidence that the Abeta peptide can act as an antioxidant, these results suggest that intraneuronal accumulation of non-oligomeric Abeta may be a compensatory response in neurons to oxidative stress in Alzheimer disease.
Nunomura
Akihiko
A
Department of Neuropsychiatry, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan. anunomura@yamanashi.ac.jp
Tamaoki
Toshio
T
Tanaka
Koich
K
Motohashi
Nobutaka
N
Nakamura
Masao
M
Hayashi
Takaaki
T
Yamaguchi
Haruyasu
H
Shimohama
Shun
S
Lee
Hyoung-gon
HG
Zhu
Xiongwei
X
Smith
Mark A
MA
Perry
George
G
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism / Q000473:pathology; D019610:Cytoprotection / Q000502:physiology; D005260:Female; D006151:Guanosine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009696:Nucleic Acids / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism
D016229:Amyloid beta-Peptides; D009696:Nucleic Acids; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D006151:Guanosine; C046215:8-hydroxyguanosine