CD22 blockade restores homeostatic microglial phagocytosis in ageing brains

John V Pluvinage; Michael S Haney; Benjamin A H Smith; Jerry Sun; Tal Iram; Liana Bonanno; Lulin Li; Davis P Lee; David W Morgens; Andrew C Yang; Steven R Shuken; David Gate; Madeleine Scott; Purvesh Khatri; Jian Luo; Carolyn R Bertozzi; Michael C Bassik; Tony Wyss-Coray

doi:10.1038/s41586-019-1088-4

CD22 blockade restores homeostatic microglial phagocytosis in ageing brains

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

Authors

John V Pluvinage^{1

2

3}, Michael S Haney³, Benjamin A H Smith^{1

4

5}, Jerry Sun³, Tal Iram³, Liana Bonanno^{1

3}, Lulin Li³, Davis P Lee³, David W Morgens⁶, Andrew C Yang^{3

5}, Steven R Shuken^{3

7}, David Gate³, Madeleine Scott^{1

8

9}, Purvesh Khatri^{8

9}, Jian Luo^{3

10}, Carolyn R Bertozzi^{4

5

7

11}, Michael C Bassik^{5

6}, Tony Wyss-Coray^{12

13

14

15

16}

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Aging / drug effects
Aging / genetics
Aging / physiology*
Animals
Brain / cytology*
Brain / drug effects
Brain / physiology
CRISPR-Associated Protein 9 / metabolism
CRISPR-Cas Systems / genetics
Cognition / drug effects
Cognition / physiology
Female
Homeostasis / drug effects*
Homeostasis / genetics
Male
Mice
Mice, Inbred C57BL
Microglia / cytology
Microglia / drug effects*
N-Acetylneuraminic Acid / chemistry
N-Acetylneuraminic Acid / pharmacology*
Phagocytosis / drug effects*
Phagocytosis / genetics
Sequence Analysis, RNA
Sialic Acid Binding Ig-like Lectin 2 / antagonists & inhibitors*
Sialic Acid Binding Ig-like Lectin 2 / genetics
Sialic Acid Binding Ig-like Lectin 2 / metabolism

Substances

CD22 protein, human
Sialic Acid Binding Ig-like Lectin 2
CRISPR-Associated Protein 9
N-Acetylneuraminic Acid

Abstract

Publication types

MeSH terms

Substances

Grants and funding