Microglia use TAM receptors to detect and engulf amyloid β plaques

被引：280

作者：

Huang, Youtong ^{[1
,2
]}

Happonen, Kaisa E. ^{[1
]}

Burrola, Patrick G. ^{[1
]}

O'Connor, Carolyn ^{[3
]}

Hah, Nasun ^{[4
]}

Huang, Ling ^{[5
]}

Nimmerjahn, Axel ^{[6
]}

Lemke, Greg ^{[1
]}

机构：

[1] Salk Inst Biol Studies, Mol Neurobiol Lab, La Jolla, CA 92037 USA

[2] Univ Calif San Diego, Div Biol Sci, La Jolla, CA USA

[3] Salk Inst Biol Studies, Flow Cytometry Core, La Jolla, CA 92037 USA

[4] Salk Inst Biol Studies, Chapman Fdn Genom Sequencing Core, La Jolla, CA 92037 USA

[5] Salk Inst Biol Studies, Razavi Newman Integrat Genom & Bioinformat Core, La Jolla, CA 92037 USA

[6] Salk Inst Biol Studies, Waitt Adv Biophoton Ctr, La Jolla, CA 92037 USA

来源：

NATURE IMMUNOLOGY | 2021年 / 22卷 / 05期

基金：

美国国家卫生研究院;

关键词：

ALZHEIMERS-DISEASE; MOUSE MODEL; A-BETA; TREM2; DEFICIENCY; TRANSGENIC MICE; BRAIN; PATHOLOGY; CELLS; PHAGOCYTOSIS; CLEARANCE;

D O I：

10.1038/s41590-021-00913-5

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

How microglia sense amyloid plaques in Alzheimer's disease has remained mysterious. Lemke and colleagues report that TAM receptor kinases are absolutely required for normal microglial recognition of, response to and phagocytosis of A beta plaques. Surprisingly, TAM-mediated microglial phagocytosis of A beta material does not constrain, but rather promotes, the formation of dense-core plaques. Two microglial TAM receptor tyrosine kinases, Axl and Mer, have been linked to Alzheimer's disease, but their roles in disease have not been tested experimentally. We find that in Alzheimer's disease and its mouse models, induced expression of Axl and Mer in amyloid plaque-associated microglia was coupled to induced plaque decoration by the TAM ligand Gas6 and its co-ligand phosphatidylserine. In the APP/PS1 mouse model of Alzheimer's disease, genetic ablation of Axl and Mer resulted in microglia that were unable to normally detect, respond to, organize or phagocytose amyloid-beta plaques. These major deficits notwithstanding, TAM-deficient APP/PS1 mice developed fewer dense-core plaques than APP/PS1 mice with normal microglia. Our findings reveal that the TAM system is an essential mediator of microglial recognition and engulfment of amyloid plaques and that TAM-driven microglial phagocytosis does not inhibit, but rather promotes, dense-core plaque development.

引用

页码：586 / +

页数：28

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