A noncompetitive BACE1 inhibitor TAK-070 ameliorates Abeta pathology and behavioral deficits in a mouse model of Alzheimer's disease.
J Neurosci
; 30(33): 11157-66, 2010 Aug 18.
Article
em En
| MEDLINE
| ID: mdl-20720123
ABSTRACT
We discovered a nonpeptidic compound, TAK-070, that inhibited BACE1, a rate-limiting protease for the generation of Abeta peptides that are considered causative for Alzheimer's disease (AD), in a noncompetitive manner. TAK-070 bound to full-length BACE1, but not to truncated BACE1 lacking the transmembrane domain. Short-term oral administration of TAK-070 decreased the brain levels of soluble Abeta, increased that of neurotrophic sAPPalpha by approximately 20%, and normalized the behavioral impairments in cognitive tests in Tg2576 mice, an APP transgenic mouse model of AD. Six-month chronic treatment decreased cerebral Abeta deposition by approximately 60%, preserving the pharmacological efficacy on soluble Abeta and sAPPalpha levels. These results support the feasibility of BACE1 inhibition with a noncompetitive inhibitor as disease-modifying as well as symptomatic therapy for AD.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Compostos de Bifenilo
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Encéfalo
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Ácido Aspártico Endopeptidases
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Transtornos Cognitivos
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Inibidores Enzimáticos
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Secretases da Proteína Precursora do Amiloide
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Doença de Alzheimer
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Naftalenos
Tipo de estudo:
Clinical_trials
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article