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Nature. 2019 Apr;568(7751):187-192. doi: 10.1038/s41586-019-1088-4. Epub 2019 Apr 3.

CD22 blockade restores homeostatic microglial phagocytosis in ageing brains.

Pluvinage JV1,2,3, Haney MS3, Smith BAH1,4,5, Sun J3, Iram T3, Bonanno L1,3, Li L3, Lee DP3, Morgens DW6, Yang AC3,5, Shuken SR3,7, Gate D3, Scott M1,8,9, Khatri P8,9, Luo J3,10, Bertozzi CR4,5,7,11, Bassik MC5,6, Wyss-Coray T12,13,14,15,16.

Author information

1
Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, USA.
2
Stem Cell Biology and Regenerative Medicine Graduate Program, Stanford University School of Medicine, Stanford, CA, USA.
3
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
4
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.
5
Chemistry, Engineering, and Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA, USA.
6
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
7
Department of Chemistry, Stanford University, Stanford, CA, USA.
8
Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA.
9
Department of Medicine, Division of Biomedical Informatics Research, Stanford University School of Medicine, Stanford, CA, USA.
10
Veterans Administration Palo Alto Healthcare System, Palo Alto, CA, USA.
11
Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
12
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA. twc@stanford.edu.
13
Chemistry, Engineering, and Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA, USA. twc@stanford.edu.
14
Veterans Administration Palo Alto Healthcare System, Palo Alto, CA, USA. twc@stanford.edu.
15
Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA. twc@stanford.edu.
16
Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA. twc@stanford.edu.

Abstract

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 α2,6-linked sialic acid, and inhibition of CD22 promotes the clearance of myelin debris, amyloid-β oligomers and α-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.

PMID:
30944478
DOI:
10.1038/s41586-019-1088-4

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