Mercaptoacetamide-based class II HDAC inhibitor lowers Aß levels and improves learning and memory in a mouse model of Alzheimer's disease.
Exp Neurol
; 239: 192-201, 2013 Jan.
Article
em En
| MEDLINE
| ID: mdl-23063601
ABSTRACT
Histone deacetylase inhibitors (HDACIs) alter gene expression epigenetically by interfering with the normal functions of HDAC. Given their ability to decrease Aß levels, HDACIs are a potential treatment for Alzheimer's disease (AD). However, it is unclear how HDACIs alter Aß levels. We developed two novel HDAC inhibitors with improved pharmacological properties, such as a longer half-life and greater penetration of the blood-brain barrier mercaptoacetamide-based class II HDACI (coded as W2) and hydroxamide-based class I and IIHDACI (coded as I2) and investigated how they affect Aß levels and cognition. HDACI W2 decreased Aß40 and Aß42 in vitro. HDACI I2 also decreased Aß40, but not Aß42. We systematically examined the molecular mechanisms by which HDACIs W2 and I2 can decrease Aß levels. HDACI W2 decreased gene expression of γ-secretase components and increased the Aß degradation enzyme Mmp2. Similarly, HDACI I2 decreased expression of ß- and γ-secretase components and increased mRNA levels of Aß degradation enzymes. HDACI W2 also significantly decreased Aß levels and rescued learning and memory deficits in aged hAPP 3xTg AD mice. Furthermore, we found that the novel HDACI W2 decreased tau phosphorylation at Thr181, an effect previously unknown for HDACIs. Collectively, these data suggest that class II HDACls may serve as a novel therapeutic strategy for AD.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tioglicolatos
/
Peptídeos beta-Amiloides
/
Histona Desacetilase 2
/
Inibidores de Histona Desacetilases
/
Doença de Alzheimer
/
Aprendizagem
/
Acetamidas
/
Memória
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Exp Neurol
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos