Oxidative stress promotes JNK-dependent amyloidogenic processing of normally expressed human APP by differential modification of alpha-, beta- and gamma-secretase expression.
Neurochem Int
; 55(7): 662-70, 2009 Dec.
Article
em En
| MEDLINE
| ID: mdl-19560504
ABSTRACT
The pathogenesis of Alzheimer disease (AD) is complex and is certain to involve diverse etiological factors, but a central role has been strongly suggested for amyloid beta-protein (Abeta), based on genetic, biochemical and neurotoxicological evidence. In contrast with the well-documented effect of genetic mutations in Abeta overproduction, not much is known about the mechanisms involved in sporadic AD (SAD) which account for more than 95% of cases. Extensive data from patients and in vivo animal models indicate that oxidative stress is one of the cardinal factors most frequently associated with this neurodegenerative disease. The aim of the present study was to explore the effect of oxidative stress on the normally expressed wild-type amyloid precursor protein (APP) in human neuroblastoma cells, which represents a more physiological model of neuronal Abeta generation. Since H(2)O(2) is the main source of the highly reactive hydroxyl radical in the brain, and FeCl(2) can stimulate oxidative stress, including the formation of the hydroxyl radical from H(2)O(2), in the present work we studied the effect of these two pro-oxidant molecules on the levels and processing of human APP by alpha-, beta- and gamma-secretase, and the role of the stress-activated kinase c-jun N-terminal kinase (JNK). We provide evidence for a dual modulation of amyloid precursor protein metabolism in differentiated human neuroblastoma cells related with a down-regulation of alpha-secretase and up-regulation of gamma-secretase, and particularly of beta-secretase and also a JNK depending Abeta generation.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Peptídeos beta-Amiloides
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Oxidantes
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Precursor de Proteína beta-Amiloide
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Estresse Oxidativo
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MAP Quinase Quinase 4
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Secretases da Proteína Precursora do Amiloide
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Peróxido de Hidrogênio
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Neurochem Int
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
México