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Neuron. 2015 Feb 4;85(3):534-48. doi: 10.1016/j.neuron.2014.12.068. Epub 2015 Jan 22.

Il10 deficiency rebalances innate immunity to mitigate Alzheimer-like pathology.

Author information

1
Zilkha Neurogenetic Institute, Department of Physiology & Biophysics, Keck School of Medicine of the University of Southern California, 1501 San Pablo Street, Los Angeles, CA 90089-2821, USA.
2
Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, LA 70808, USA.
3
Zilkha Neurogenetic Institute, Department of Physiology & Biophysics, Keck School of Medicine of the University of Southern California, 1501 San Pablo Street, Los Angeles, CA 90089-2821, USA. Electronic address: ttown@usc.edu.

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 Aβ 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 Aβ phagocytosis, while exogenous IL-10 had the converse effect. Il10 deficiency also partially overcame inhibition of microglial Aβ 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.

PMID:
25619654
PMCID:
PMC4352138
DOI:
10.1016/j.neuron.2014.12.068
[Indexed for MEDLINE]
Free PMC Article
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