Journal
NEURON
Volume 85, Issue 3, Pages 534-548Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2014.12.068
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Funding
- NIH National Research Service Award [1F31NS083339-01A1]
- National Institute on Aging [5R00AG029726-04, 3R00AG029726-04S1]
- National Institute on Neurologic Disorders and Stroke [1R01NS076794-01]
- Alzheimer's Association Zenith Fellows Award [ZEN-10-174633]
- American Federation of Aging Research/Ellison Medical Foundation Julie Martin Mid-Career Award in Aging Research [M11472]
- Zilkha Neurogenetic Institute
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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 Ab 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 A beta phagocytosis, while exogenous IL-10 had the converse effect. Il10 deficiency also partially overcame inhibition of microglial Ab 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.
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