Increased efflux of amyloid-ß peptides through the blood-brain barrier by muscarinic acetylcholine receptor inhibition reduces pathological phenotypes in mouse models of brain amyloidosis.
J Alzheimers Dis
; 38(4): 767-86, 2014.
Article
em En
| MEDLINE
| ID: mdl-24072071
ABSTRACT
The formation and accumulation of toxic amyloid-ß peptides (Aß) in the brain may drive the pathogenesis of Alzheimer's disease. Accordingly, disease-modifying therapies for Alzheimer's disease and related disorders could result from treatments regulating Aß homeostasis. Examples are the inhibition of production, misfolding, and accumulation of Aß or the enhancement of its clearance. Here we show that oral treatment with ACI-91 (Pirenzepine) dose-dependently reduced brain Aß burden in AßPPPS1, hAßPPSL, and AßPP/PS1 transgenic mice. A possible mechanism of action of ACI-91 may occur through selective inhibition of muscarinic acetylcholine receptors (AChR) on endothelial cells of brain microvessels and enhanced Aß peptide clearance across the blood-brain barrier. One month treatment with ACI-91 increased the clearance of intrathecally-injected Aß in plaque-bearing mice. ACI-91 also accelerated the clearance of brain-injected Aß in blood and peripheral tissues by favoring its urinal excretion. A single oral dose of ACI-91 reduced the half-life of interstitial Aß peptide in pre-plaque mhAßPP/PS1d mice. By extending our studies to an in vitro model, we showed that muscarinic AChR inhibition by ACI-91 and Darifenacin augmented the capacity of differentiated endothelial monolayers for active transport of Aß peptide. Finally, ACI-91 was found to consistently affect, in vitro and in vivo, the expression of endothelial cell genes involved in Aß transport across the Blood Brain Brain (BBB). Thus increased Aß clearance through the BBB may contribute to reduced Aß burden and associated phenotypes. Inhibition of muscarinic AChR restricted to the periphery may present a therapeutic advantage as it avoids adverse central cholinergic effects.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fenótipo
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Barreira Hematoencefálica
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Peptídeos beta-Amiloides
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Receptores Muscarínicos
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Angiopatia Amiloide Cerebral
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Antagonistas Muscarínicos
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Modelos Animais de Doenças
Limite:
Animals
Idioma:
En
Revista:
J Alzheimers Dis
Assunto da revista:
GERIATRIA
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NEUROLOGIA
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Suíça