CD22 blockade restores homeostatic microglial phagocytosis in ageing brains

被引：337

作者：

Pluvinage, John V. ^{[1
,2
,3
]}

Haney, Michael S. ^{[3
]}

Smith, Benjamin A. H. ^{[1
,4
,5
]}

Sun, Jerry ^{[3
]}

Iram, Tal ^{[3
]}

Bonanno, Liana ^{[1
,3
]}

Li, Lulin ^{[3
]}

Lee, Davis P. ^{[3
]}

Morgens, David W. ^{[6
]}

Yang, Andrew C. ^{[3
,5
]}

Shuken, Steven R. ^{[3
,7
]}

Gate, David ^{[3
]}

Scott, Madeleine ^{[1
,8
,9
]}

Khatri, Purvesh ^{[8
,9
]}

Luo, Jian ^{[3
,10
]}

Bertozzi, Carolyn R. ^{[4
,5
,7
,11
]}

Bassik, Michael C. ^{[5
,6
]}

Wyss-Coray, Tony ^{[3
,5
,10
,12
,13
]}

机构：

[1] Stanford Univ, Sch Med, Med Scientist Training Program, Stanford, CA 94305 USA

[2] Stanford Univ, Sch Med, Stem Cell Biol & Regenerat Med Grad Program, Stanford, CA 94305 USA

[3] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA

[4] Stanford Univ, Sch Med, Dept Chem & Syst Biol, Stanford, CA 94305 USA

[5] Stanford Univ, Chem Engn & Med Human Hlth ChEM H, Stanford, CA 94305 USA

[6] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA

[7] Stanford Univ, Dept Chem, Stanford, CA 94305 USA

[8] Stanford Univ, Sch Med, Inst Immun Transplantat & Infect, Stanford, CA 94305 USA

[9] Stanford Univ, Dept Med, Sch Med, Div Biomed Informat Res, Stanford, CA 94305 USA

[10] Vet Adm Palo Alto Healthcare Syst, Palo Alto, CA 94304 USA

[11] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA

[12] Stanford Univ, Sch Med, Paul F Glenn Ctr Biol Aging, Stanford, CA 94305 USA

[13] Stanford Univ, Wu Tsai Neurosci Inst, Stanford, CA 94305 USA

来源：

NATURE | 2019年 / 568卷 / 7751期

关键词：

ALZHEIMERS-DISEASE; CLEARANCE PATHWAYS; CELLS; MOUSE; RNA; EXPRESSION; TURNOVER; NEURONS; DRIVES; AGE;

D O I：

10.1038/s41586-019-1088-4

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Microglia maintain homeostasis in the central nervous system through phagocytic clearance of protein aggregates and cellular debris. This function deteriorates during ageing and neurodegenerative disease, concomitant with cognitive decline. However, the mechanisms of impaired microglial homeostatic function and the cognitive effects of restoring this function remain unknown. We combined CRISPR-Cas9 knockout screens with RNA sequencing analysis to discover age-related genetic modifiers of microglial phagocytosis. These screens identified CD22, a canonical B cell receptor, as a negative regulator of phagocytosis that is upregulated on aged microglia. CD22 mediates the anti-phagocytic effect of alpha 2,6-linked sialic acid, and inhibition of CD22 promotes the clearance of myelin debris, amyloid-beta oligomers and alpha-synuclein fibrils in vivo. Long-term central nervous system delivery of an antibody that blocks CD22 function reprograms microglia towards a homeostatic transcriptional state and improves cognitive function in aged mice. These findings elucidate a mechanism of age-related microglial impairment and a strategy to restore homeostasis in the ageing brain.

引用

页码：187 / +

页数：23

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