NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice.
Nature
; 493(7434): 674-8, 2013 Jan 31.
Article
en En
| MEDLINE
| ID: mdl-23254930
ABSTRACT
Alzheimer's disease is the world's most common dementing illness. Deposition of amyloid-ß peptide drives cerebral neuroinflammation by activating microglia. Indeed, amyloid-ß activation of the NLRP3 inflammasome in microglia is fundamental for interleukin-1ß maturation and subsequent inflammatory events. However, it remains unknown whether NLRP3 activation contributes to Alzheimer's disease in vivo. Here we demonstrate strongly enhanced active caspase-1 expression in human mild cognitive impairment and brains with Alzheimer's disease, suggesting a role for the inflammasome in this neurodegenerative disease. Nlrp3(-/-) or Casp1(-/-) mice carrying mutations associated with familial Alzheimer's disease were largely protected from loss of spatial memory and other sequelae associated with Alzheimer's disease, and demonstrated reduced brain caspase-1 and interleukin-1ß activation as well as enhanced amyloid-ß clearance. Furthermore, NLRP3 inflammasome deficiency skewed microglial cells to an M2 phenotype and resulted in the decreased deposition of amyloid-ß in the APP/PS1 model of Alzheimer's disease. These results show an important role for the NLRP3/caspase-1 axis in the pathogenesis of Alzheimer's disease, and suggest that NLRP3 inflammasome inhibition represents a new therapeutic intervention for the disease.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Encéfalo
/
Proteínas Portadoras
/
Enfermedad de Alzheimer
Límite:
Aged
/
Aged80
/
Animals
/
Humans
Idioma:
En
Revista:
Nature
Año:
2013
Tipo del documento:
Article
País de afiliación:
Alemania