Sodium channel cleavage is associated with aberrant neuronal activity and cognitive deficits in a mouse model of Alzheimer's disease.
J Neurosci
; 33(16): 7020-6, 2013 Apr 17.
Article
em En
| MEDLINE
| ID: mdl-23595759
ABSTRACT
BACE1 is the rate-limiting enzyme that cleaves amyloid precursor protein (APP) to produce the amyloid ß peptides that accumulate in Alzheimer's disease (AD). BACE1, which is elevated in AD patients and APP transgenic mice, also cleaves the ß2-subunit of voltage-gated sodium channels (Navß2). Although increased BACE1 levels are associated with Navß2 cleavage in AD patients, whether Navß2 cleavage occurs in APP mice had not yet been examined. Such a finding would be of interest because of its potential impact on neuronal activity previous studies demonstrated that BACE1-overexpressing mice exhibit excessive cleavage of Navß2 and reduced sodium current density, but the phenotype associated with loss of function mutations in either Navß-subunits or pore-forming α-subunits is epilepsy. Because mounting evidence suggests that epileptiform activity may play an important role in the development of AD-related cognitive deficits, we examined whether enhanced cleavage of Navß2 occurs in APP transgenic mice, and whether it is associated with aberrant neuronal activity and cognitive deficits. We found increased levels of BACE1 expression and Navß2 cleavage fragments in cortical lysates from APP transgenic mice, as well as associated alterations in Nav1.1α expression and localization. Both pyramidal neurons and inhibitory interneurons exhibited evidence of increased Navß2 cleavage. Moreover, the magnitude of alterations in sodium channel subunits was associated with aberrant EEG activity and impairments in the Morris water maze. Together, these results suggest that altered processing of voltage-gated sodium channels may contribute to aberrant neuronal activity and cognitive deficits in AD.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Canais de Sódio
/
Transtornos Cognitivos
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Doença de Alzheimer
/
Neurônios
Tipo de estudo:
Prognostic_studies
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Risk_factors_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article