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CD22 blockade restores homeostatic microglial phagocytosis in ageing brains.
Pluvinage, John V; Haney, Michael S; Smith, Benjamin A H; Sun, Jerry; Iram, Tal; Bonanno, Liana; Li, Lulin; Lee, Davis P; Morgens, David W; Yang, Andrew C; Shuken, Steven R; Gate, David; Scott, Madeleine; Khatri, Purvesh; Luo, Jian; Bertozzi, Carolyn R; Bassik, Michael C; Wyss-Coray, Tony.
  • Pluvinage JV; Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, USA.
  • Haney MS; Stem Cell Biology and Regenerative Medicine Graduate Program, Stanford University School of Medicine, Stanford, CA, USA.
  • Smith BAH; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Sun J; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Iram T; Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, USA.
  • Bonanno L; Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.
  • Li L; Chemistry, Engineering, and Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA, USA.
  • Lee DP; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Morgens DW; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Yang AC; Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, USA.
  • Shuken SR; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Gate D; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Scott M; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Khatri P; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
  • Luo J; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Bertozzi CR; Chemistry, Engineering, and Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA, USA.
  • Bassik MC; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Wyss-Coray T; Department of Chemistry, Stanford University, Stanford, CA, USA.
Nature ; 568(7751): 187-192, 2019 04.
Article en En | MEDLINE | ID: mdl-30944478
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-ß 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.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Fagocitosis / Encéfalo / Envejecimiento / Microglía / Ácido N-Acetilneuramínico / Lectina 2 Similar a Ig de Unión al Ácido Siálico / Homeostasis Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Año: 2019 Tipo del documento: Article
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Fagocitosis / Encéfalo / Envejecimiento / Microglía / Ácido N-Acetilneuramínico / Lectina 2 Similar a Ig de Unión al Ácido Siálico / Homeostasis Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Año: 2019 Tipo del documento: Article