Targeting the HDAC2/HNF-4A/miR-101b/AMPK Pathway Rescues Tauopathy and Dendritic Abnormalities in Alzheimer's Disease.
Mol Ther
; 25(3): 752-764, 2017 03 01.
Article
en En
| MEDLINE
| ID: mdl-28202389
ABSTRACT
Histone deacetylase 2 (HDAC2) plays a major role in the epigenetic regulation of gene expression. Previous studies have shown that HDAC2 expression is strongly increased in Alzheimer's disease (AD), a major neurodegenerative disorder and the most common form of dementia. Moreover, previous studies have linked HDAC2 to Aß overproduction in AD; however, its involvement in tau pathology and other memory-related functions remains unclear. Here, we show that increased HDAC2 levels strongly correlate with phosphorylated tau in a mouse model of AD. HDAC2 overexpression induced AD-like tau hyperphosphorylation and aggregation, which were accompanied by a loss of dendritic complexity and spine density. The ectopic expression of HDAC2 resulted in the deacetylation of the hepatocyte nuclear factor 4α (HNF-4A) transcription factor, which disrupted its binding to the miR-101b promoter. The suppression of miR-101b caused an upregulation of its target, AMP-activated protein kinase (AMPK). The introduction of miR-101b mimics or small interfering RNAs (siRNAs) against AMPK blocked HDAC2-induced tauopathy and dendritic impairments in vitro. Correspondingly, miR-101b mimics or AMPK siRNAs rescued tau pathology, dendritic abnormalities, and memory deficits in AD mice. Taken together, the current findings implicate the HDAC2/miR-101/AMPK pathway as a critical mediator of AD pathogenesis. These studies also highlight the importance of epigenetics in AD and provide novel therapeutic targets.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Tauopatías
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MicroARNs
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Factor Nuclear 4 del Hepatocito
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Proteínas Quinasas Activadas por AMP
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Histona Desacetilasa 2
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Enfermedad de Alzheimer
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Mol Ther
Asunto de la revista:
BIOLOGIA MOLECULAR
/
TERAPEUTICA
Año:
2017
Tipo del documento:
Article