Il10 deficiency rebalances innate immunity to mitigate Alzheimer-like pathology

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 mousedeficient in Il10 (APP/PS1+Il10-/-). Quantitativeinsilico 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. Invitro 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 Aβuptake by human Apolipoprotein E. Finally, the IL-10 signaling pathway was abnormally elevated inAD patient brains. Our results suggest that "rebalancing" innate immunity by blocking the IL-10 anti-inflammatory response may be therapeutically relevant for AD.