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Human brain sialoglycan ligand for CD33, a microglial inhibitory Siglec implicated in Alzheimer's disease.

Authors
  • Gonzalez-Gil, Anabel1
  • Porell, Ryan N1
  • Fernandes, Steve M1
  • Maenpaa, Eila1
  • August Li, T1
  • Li, Tong2
  • Wong, Philip C3
  • Aoki, Kazuhiro4
  • Tiemeyer, Michael4
  • Yu, Zaikuan J1
  • Orsburn, Benjamin C1
  • Bumpus, Namandjé N1
  • Matthews, Russell T5
  • Schnaar, Ronald L6
  • 1 Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • 2 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • 3 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • 4 Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia, USA. , (Georgia)
  • 5 Department of Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse, New York, USA.
  • 6 Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Electronic address: [email protected]
Type
Published Article
Journal
Journal of Biological Chemistry
Publisher
American Society for Biochemistry and Molecular Biology
Publication Date
Apr 19, 2022
Pages
101960–101960
Identifiers
DOI: 10.1016/j.jbc.2022.101960
PMID: 35452678
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Alzheimer's disease (AD) is characterized by accumulation of misfolded proteins. Genetic studies implicate microglia, brain-resident phagocytic immune cells, in AD pathogenesis. As positive effectors, microglia clear toxic proteins, whereas as negative effectors they release proinflammatory mediators. An imbalance of these functions contributes to AD progression. Polymorphisms of human CD33, an inhibitory microglial receptor, are linked to AD susceptibility; higher CD33 expression correlates with increased AD risk. CD33, also called Siglec-3, is a member of the sialic acid-binding immunoglobulin-type lectin (Siglec) family of immune regulatory receptors. Siglec-mediated inhibition is initiated by binding to complementary sialoglycan ligands in the tissue environment. Here, we identify a single sialoglycoprotein in human cerebral cortex that binds CD33 as well as Siglec-8, the most abundant Siglec on human microglia. The ligand, which we term RPTPζS3L, is composed of sialylated keratan sulfate chains carried on a minor isoform/glycoform of receptor protein tyrosine phosphatase zeta (RPTPζ, phosphacan) and is found in the extracellular milieu of the human brain parenchyma. Brains from human AD donors had 2-fold higher levels of RPTPζS3L than age-matched control donors, raising the possibility that RPTPζS3L overexpression limits misfolded protein clearance contributing to AD pathology. Mice express the same structure, a sialylated keratan sulfate RPTPζ isoform, that binds mouse Siglec-F and cross-reacts with human CD33 and Siglec-8. Brains from mice engineered to lack RPTPζ, the sialyltransferase St3gal4, or the keratan sulfate sulfotransferase Chst1 lacked Siglec binding, establishing the ligand structure. The unique CD33 and Siglec-8 ligand, RPTPζS3L, may contribute to Alzheimer's disease progression. Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

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