Pharmacological inhibition of G9a/GLP restores cognition and reduces oxidative stress, neuroinflammation and ß-Amyloid plaques in an early-onset Alzheimer's disease mouse model.
Aging (Albany NY)
; 11(23): 11591-11608, 2019 12 04.
Article
en En
| MEDLINE
| ID: mdl-31804189
ABSTRACT
The implication of epigenetic mechanisms in Alzheimer's disease (AD) has been demonstrated in several studies. UNC0642, a specific and potent inhibitor of methyltransferase activity G9a/GLP (G9a-like) complex, was evaluated in the 5XFAD mouse model. UNC0642 treatment rescued 5XFAD cognition impairment, reduced DNA-methylation (5-mC), increased hydroxymethylation (5-hmC), and decreased the di-methylation of lysine 9 of histone H3 (H3K9me2) levels in the hippocampus. Increases in the Nuclear Factor erythroid-2-Related Factor 2 (NRF2), Heme oxygenase decycling 1 (Hmox1) gene expression, and diminution in Reactive Oxygen Species (ROS) were also reported. Moreover, neuroinflammatory markers, such as Interleukin 6 (Il-6), Tumor necrosis factor-alpha (Tnf-α) gene expression, and Glial fibrillary acidic protein (GFAP) immunofluorescence were reduced by UNC0642 treatment. An increase in Nerve growth factor (Ngf), Nerve growth factor inducible (Vgf) gene expression, Brain-derived neurotrophic factor (BDNF), and Synaptophysin (SYN) were found after UNC0642 treatment. Importantly, a reduction in ß-amyloid plaques was also observed. In conclusion, our work demonstrates that the inhibition of the G9a/GLP complex by UNC0642 delivered significant neuroprotective effects in 5XFAD mice, point out G9a/GLP as a new target for AD.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Quinazolinas
/
N-Metiltransferasa de Histona-Lisina
/
Cognición
/
Estrés Oxidativo
/
Péptidos Similares al Glucagón
/
Enfermedad de Alzheimer
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Aging (Albany NY)
Asunto de la revista:
GERIATRIA
Año:
2019
Tipo del documento:
Article
País de afiliación:
España