Immunocytochemical evidence that amyloid beta (1-42) impairs endogenous antioxidant systems in vivo.
Amyloid beta, the major constituent of the senile plaques in the brains of patients with Alzheimer's disease, is cytotoxic to neurons and has a central role in the pathogenesis of the disease. We have previously demonstrated that potent antioxidants idebenone and alpha-tocopherol prevent learning and memory impairment in rats which received a continuous intracerebroventricular infusion of amyloid beta, suggesting a role for oxidative stress in amyloid beta-induced learning and memory impairment. To test the hypothesis, in the present study, we investigated alterations in the immunoreactivity of endogenous antioxidant systems such as mitochondrial Mn-superoxide dismutase, glutathione, glutathione peroxidase and glutathione-S-transferase following the continuous intracerebroventricular infusion of amyloid beta for 2 weeks. The infusion of amyloid beta (1-42) resulted in a significant reduction of the immunoreactivity of these antioxidant substances in such brain areas as the hippocampus, parietal cortex, piriform cortex, substantia nigra and thalamus although the same treatment with amyloid beta (40-1) had little effect. The alterations induced by amyloid beta (1-42) were not uniform, but rather specific for each immunoreactive substance in a brain region-dependent manner. These results demonstrate a cytological effect of oxidative stress induced by amyloid beta (1-42) infusion. Furthermore, our findings may indicate a heterogeneous susceptibility to the oxidative stress produced by amyloid beta.
Kim
H-C
HC
Department of Pharmacy, College of Pharmacy, Kangwon National University, Korea Institute of Drug Abuse, Chunchon 200-701, South Korea.
Yamada
K
K
Nitta
A
A
Olariu
A
A
Tran
M H
MH
Mizuno
M
M
Nakajima
A
A
Nagai
T
T
Kamei
H
H
Jhoo
W-K
WK
Im
D-H
DH
Shin
E-J
EJ
Hjelle
O P
OP
Ottersen
O P
OP
Park
S C
SC
Kato
K
K
Mirault
M-E
ME
Nabeshima
T
T
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D003720:Densitometry / Q000379:methods; D004333:Drug Administration Routes / Q000662:veterinary; D005978:Glutathione / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism*; D007150:Immunohistochemistry / Q000379:methods; D007260:Infusion Pumps; D008297:Male; D010446:Peptide Fragments / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000378:metabolism*; D013997:Time Factors
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005982:Glutathione Transferase; D005978:Glutathione