Il10 deficiency rebalances innate immunity to mitigate Alzheimer-like pathology.
Neuron
; 85(3): 534-48, 2015 Feb 04.
Article
em En
| MEDLINE
| ID: mdl-25619654
ABSTRACT
The impact of inflammation suppressor pathways on Alzheimer's disease (AD) evolution remains poorly understood. Human genetic evidence suggests involvement of the cardinal anti-inflammatory cytokine, interleukin-10 (IL10). We crossed the APP/PS1 mouse model of cerebral amyloidosis with a mouse deficient in Il10 (APP/PS1(+)Il10(-/-)). Quantitative in silico 3D modeling revealed activated Aß phagocytic microglia in APP/PS1(+)Il10(-/-) mice that restricted cerebral amyloidosis. Genome-wide RNA sequencing of APP/PS1(+)Il10(-/-) brains showed selective modulation of innate immune genes that drive neuroinflammation. Il10 deficiency preserved synaptic integrity and mitigated cognitive disturbance in APP/PS1 mice. In vitro knockdown of microglial Il10-Stat3 signaling endorsed Aß phagocytosis, while exogenous IL-10 had the converse effect. Il10 deficiency also partially overcame inhibition of microglial Aß uptake by human Apolipoprotein E. Finally, the IL-10 signaling pathway was abnormally elevated in AD patient brains. Our results suggest that "rebalancing" innate immunity by blocking the IL-10 anti-inflammatory response may be therapeutically relevant for AD.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Interleucina-10
/
Doença de Alzheimer
/
Imunidade Inata
Tipo de estudo:
Prognostic_studies
Limite:
Aged
/
Aged80
/
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Neuron
Ano de publicação:
2015
Tipo de documento:
Article