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Assessing Microglial Phagocytosis of Myelin Debris in vitro Under Repeated Magnetic Stimulation
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CD22 blockade restores homeostatic microglial phagocytosis in ageing brains

John V Pluvinage1,2,3, Michael S Haney3, Benjamin A H Smith1,4,5

  • 1Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, USA.

Nature
|April 5, 2019
PubMed

Insights

Researchers discovered that inhibiting CD22, a receptor found on aged microglia, restores their ability to clear waste. This intervention improves cognitive function in aging mice, offering a potential strategy for brain health.

Area of Science:

  • Neuroscience
  • Immunology
  • Aging Research

Background:

  • Microglia are crucial for central nervous system (CNS) homeostasis, clearing debris via phagocytosis.
  • Microglial phagocytic function declines with age and in neurodegenerative diseases, correlating with cognitive decline.
  • Mechanisms of impaired microglial function and cognitive benefits of restoration are largely unknown.

Purpose of the Study:

  • To identify age-related genetic modifiers of microglial phagocytosis.
  • To investigate the role of CD22 in microglial function during aging.
  • To evaluate the therapeutic potential of CD22 inhibition for cognitive aging.

Main Methods:

  • CRISPR-Cas9 knockout screens combined with RNA sequencing to identify genetic modifiers.
  • In vivo studies using antibody-mediated CD22 blockade.
  • Assessment of microglial phagocytosis of various debris in aged mice.
  • Evaluation of cognitive function in aged mice after CD22 inhibition.

Main Results:

  • CD22, a B cell receptor, was identified as a negative regulator of microglial phagocytosis, upregulated in aged microglia.
  • CD22 mediates the inhibitory effects of α2,6-linked sialic acid on phagocytosis.
  • CD22 inhibition enhanced clearance of myelin debris, amyloid-β, and α-synuclein in vivo.
  • Long-term CNS delivery of anti-CD22 antibody reprogrammed microglia to a homeostatic state and improved cognitive function in aged mice.

Conclusions:

  • CD22 is a key mediator of age-related microglial phagocytic impairment.
  • Inhibiting CD22 restores microglial homeostatic function and enhances cognitive performance in aging.
  • Targeting CD22 presents a promising therapeutic strategy for age-related cognitive decline and neurodegeneration.

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