Beta-Amyloid Directly Inhibits Human alfa beta2-Nicotinic Acetylcholine Receptor Function
In. II International Congress on Neuroregeneration. Proceedings (selected papers). Rio de Janeiro, UFRJ, 2004. p.17-20, ilus, tab.
Monography
em En
| LILACS
| ID: lil-682588
Biblioteca responsável:
BR408.1
Localização: BR408.1; CD616.8, P963, 2004
ABSTRACT
Amyloid-Beta (Aβ) accumulation and aggregation are thought to contribute to the pathogenesis of Alzheimers disease (AD). In AD, there also is a selective decrease in numbers of radioligand binding sites corresponding to the most abundant nicotinic acetylcholine receptor (nAChR) subtype, which contains human α4 and β2 subunits (α4β2-nAChR). However, relationships between these phenomena are uncertain, and effects of Aβ on human α4β2-nAChR function have not been investigated in detail. We created SH-EP1 cells stably transfected to heterologously express human α4β2- or α7-nAChR subtypes. Whole-cell current recording confirmed heterologous expression of functional α4β2-nAChR with characteristic responses to nicotinic agonists or antagonists. Nicotine-induced whole-cell currents were suppressed by Aβ1−42 in a dose-dependent manner. Functional inhibition was selective for Aβ1−42 compared to functionally-inactive, control peptide Aβ40-1, but was mimicked by Aβ1-40. Aβ1-42-mediated inhibition of α4β2-nAChR function was non-competitive, voltage¬independent, and use-independent. Pre-loading of cells with GDP-β-S failed to prevent Aβ1-42 induced inhibition, suggesting that the down-regulation of α4β2-nAChR function by Aβ1-42 is not mediated by nAChR internalization. Sensitivity to Aβ1-42 antagonism at 1 nM was evident for α4β 2-nAChR, but not for heterologously expressed, human α7-nAChR, although both nAChR subtypes were functionally inhibited by 100 nM Aβ1-42, with the magnitude of functional block being higher for 100 nM Aβ1-42 acting at α7-nAChR. These findings suggest that α4β2-nAChR are sensitive and perhaps pathophysiologically-relevant targets for Aβ neurotoxicity in AD.
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Coleções:
01-internacional
Base de dados:
LILACS
Assunto principal:
Acetilcolina
/
Peptídeos beta-Amiloides
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Doença de Alzheimer
/
Neurologia
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Nicotina
Idioma:
En
Ano de publicação:
2004
Tipo de documento:
Congress and conference
/
Monography
País de publicação:
Brasil