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J Neurochem ; 110(5): 1377-87, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19519664

RESUMO

Alzheimer's disease (AD) is hypothesized to result from elevated brain levels of beta-amyloid peptide (Abeta) which is the main component of plaques found in AD brains and which cause memory impairment in mice. Therefore, there has been a major focus on the development of inhibitors of the Abeta producing enzymes gamma-secretase and beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1). In this study, we investigated the Abeta-lowering effects of the BACE1 inhibitor LY2434074 in vitro and in vivo, comparing it to the well characterized gamma-secretase inhibitor LY450139. We sampled interstitial fluid Abeta from awake APPswe/PS1dE9 AD mice by in vivo Abeta microdialysis. In addition, we measured levels of endogenous brain Abeta extracted from wildtype C57BL/6 mice. In our in vitro assays both compounds showed similar Abeta-lowering effects. However, while systemic administration of LY450139 resulted in transient reduction of Abeta in both in vivo models, we were unable to show any Abeta-lowering effect by systemic administration of the BACE1 inhibitor LY2434074 despite brain exposure exceeding the in vitro IC(50) value several fold. In contrast, significant reduction of 40-50% of interstitial fluid Abeta and wildtype cortical Abeta was observed when infusing LY2434074 directly into the brain by means of reverse microdialysis or by dosing the BACE1 inhibitor to p-glycoprotein (p-gp) mutant mice. The effects seen in p-gp mutant mice and subsequent data from our cell-based p-gp transport assay suggested that LY2434074 is a p-gp substrate. This may partly explain why BACE1 inhibition by LY2434074 has lower in vivo efficacy, with respect to decreased Abeta40 levels, compared with gamma-secretase inhibition by LY450139.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Encéfalo/enzimologia , Alanina/análogos & derivados , Alanina/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Ácido Aspártico Endopeptidases/metabolismo , Azepinas/farmacologia , Encéfalo/efeitos dos fármacos , Linhagem Celular , Células Cultivadas , Cães , Relação Dose-Resposta a Droga , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Inibidores de Proteases/farmacologia
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