Il10 Deficiency Rebalances Innate Immunity to Mitigate Alzheimer-Like Pathology

被引：350

作者：

Guillot-Sestier, Marie-Victoire ^{[1
]}

Doty, Kevin R. ^{[1
]}

Gate, David ^{[1
]}

Rodriguez, Javier, Jr. ^{[1
]}

Leung, Brian P. ^{[1
]}

Rezai-Zadeh, Kavon ^{[2
]}

Town, Terrence ^{[1
]}

机构：

[1] Univ So Calif, Keck Sch Med, Dept Physiol & Biophys, Zilkha Neurogenet Inst, Los Angeles, CA 90089 USA

[2] Louisiana State Univ, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA

来源：

NEURON | 2015年 / 85卷 / 03期

关键词：

AMYLOID-BETA-PEPTIDE; PROMOTER REGION POLYMORPHISMS; MOUSE MODEL; MICROGLIAL ACTIVATION; INTERLEUKIN-10; GENE; C4B-BINDING PROTEIN; MEMORY DEFICITS; PLAQUE BURDEN; IN-VIVO; DISEASE;

D O I：

10.1016/j.neuron.2014.12.068

中图分类号：

Q189 [神经科学];

学科分类号：

071006 [神经生物学];

摘要：

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.

引用

页码：534 / 548

页数：15

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