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

Nature, 2019, vol. 568, issue 7751, 187-192

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1088-4

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