CD22 blockade restores homeostatic microglial phagocytosis in ageing brains.

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

Journal

Nature
ISSN: 1476-4687
Titre abrégé: Nature
Pays: England
ID NLM: 0410462

Informations de publication

Date de publication:
04 2019
Historique:
received: 23 08 2018
accepted: 01 03 2019
pubmed: 5 4 2019
medline: 2 11 2019
entrez: 5 4 2019
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s41586-019-1088-4 PMID: 30944478 PMC: PMC6574119
pubmed: 30944478
doi: 10.1038/s41586-019-1088-4
pii: 10.1038/s41586-019-1088-4
pmc: PMC6574119
mid: NIHMS1523028
doi:

Substances chimiques

CD22 protein, human 0
Sialic Acid Binding Ig-like Lectin 2 0
CRISPR-Associated Protein 9 EC 3.1.-
N-Acetylneuraminic Acid GZP2782OP0

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

187-192

Subventions

Organisme : NIGMS NIH HHS
ID : R01 GM059907
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007365
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG045034
Pays : United States
Organisme : NIH HHS
ID : S10 OD020141
Pays : United States
Organisme : NHGRI NIH HHS
ID : T32 HG000044
Pays : United States
Organisme : NIA NIH HHS
ID : F30 AG060638
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM120007
Pays : United States
Organisme : NIA NIH HHS
ID : DP1 AG053015
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA227942
Pays : United States

Commentaires et corrections

Type : CommentIn

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Auteurs

John V Pluvinage (JV)

Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, USA.
Stem Cell Biology and Regenerative Medicine Graduate Program, Stanford University School of Medicine, Stanford, CA, USA.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.

Michael S Haney (MS)

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.

Benjamin A H Smith (BAH)

Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, USA.
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.
Chemistry, Engineering, and Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA, USA.

Jerry Sun (J)

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.

Tal Iram (T)

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.

Liana Bonanno (L)

Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, USA.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.

Lulin Li (L)

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.

Davis P Lee (DP)

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.

David W Morgens (DW)

Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.

Andrew C Yang (AC)

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Chemistry, Engineering, and Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA, USA.

Steven R Shuken (SR)

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Department of Chemistry, Stanford University, Stanford, CA, USA.

David Gate (D)

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.

Madeleine Scott (M)

Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, USA.
Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA.
Department of Medicine, Division of Biomedical Informatics Research, Stanford University School of Medicine, Stanford, CA, USA.

Purvesh Khatri (P)

Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA.
Department of Medicine, Division of Biomedical Informatics Research, Stanford University School of Medicine, Stanford, CA, USA.

Jian Luo (J)

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Veterans Administration Palo Alto Healthcare System, Palo Alto, CA, USA.

Carolyn R Bertozzi (CR)

Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.
Chemistry, Engineering, and Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA, USA.
Department of Chemistry, Stanford University, Stanford, CA, USA.
Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.

Michael C Bassik (MC)

Chemistry, Engineering, and Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA, USA.
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.

Tony Wyss-Coray (T)

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA. twc@stanford.edu.
Chemistry, Engineering, and Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA, USA. twc@stanford.edu.
Veterans Administration Palo Alto Healthcare System, Palo Alto, CA, USA. twc@stanford.edu.
Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA. twc@stanford.edu.
Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA. twc@stanford.edu.

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Classifications MeSH

questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Vieillissement › CD22 blockade restores homeostatic microglial...
questionsmedicales.fr › Eucaryotes › Animaux › CD22 blockade restores homeostatic microglial...
questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › CD22 blockade restores homeostatic microglial...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines associées aux CRISPR › Protéine-9 associée à CRISPR › CD22 blockade restores homeostatic microglial...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Épigenèse génétique › Extinction de l'expression des gènes › Systèmes CRISPR-Cas › CD22 blockade restores homeostatic microglial...
questionsmedicales.fr › Phénomènes psychologiques › Processus mentaux › Cognition › CD22 blockade restores homeostatic microglial...
questionsmedicales.fr › Phénomènes physiologiques › Homéostasie › CD22 blockade restores homeostatic microglial...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › CD22 blockade restores homeostatic microglial...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › CD22 blockade restores homeostatic microglial...
questionsmedicales.fr › Cellules › Névroglie › Microglie › CD22 blockade restores homeostatic microglial...
questionsmedicales.fr › Glucides › Oses acides › Acides neuraminiques › Acides sialiques › Acide N-acétyl-neuraminique › CD22 blockade restores homeostatic microglial...
questionsmedicales.fr › Phénomènes du système immunitaire › Phagocytose › CD22 blockade restores homeostatic microglial...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Analyse de séquence d'ARN › CD22 blockade restores homeostatic microglial...
questionsmedicales.fr › Facteurs biologiques › Antigènes › Antigènes de surface › Molécules d'adhérence cellulaire › Lectine-2 de type Ig liant l'acide sialique › CD22 blockade restores homeostatic microglial...