Definition of the contribution of an Osteopontin-producing CD11c+ microglial subset to Alzheimer’s disease

Yiguo Qiu, Xianli Shen, Orly Ravid, Dana Atrakchi, Daniel Rand, Andrew E. Wight, Hye Jung Kim, Sigal Liraz-Zaltsman, Itzik Cooper, Michal Schnaider Beeri, Harvey Cantor*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Alzheimer’s disease (AD) is the most common form of incurable dementia and represents a critical public health issue as the world’s population ages. Although microglial dysregulation is a cardinal feature of AD, the extensive heterogeneity of these immunological cells in the brain has impeded our understanding of their contribution to this disease. Here, we identify a pathogenic microglial subset which expresses the CD11c surface marker as the sole producer of Osteopontin (OPN) in the 5XFAD mouse model of AD. OPN production divides Disease-Associated Microglia (DAM) into two functionally distinct subsets, i.e., a protective CD11c+OPN subset that robustly ingests amyloid β (Aβ) in a noninflammatory fashion and a pathogenic CD11c+OPN+ subset that produces proinflammatory cytokines and fails to ingest significant amounts of Aβ. Genetic ablation of OPN or administration of monoclonal anti-OPN antibody to 5XFAD mice reduces proinflammatory microglia, plaque formation, and numbers of dystrophic neurites and results in improved cognitive function. Analysis of brain tissue from AD patients indicates that levels of OPN-producing CD11c+ microglia correlate strongly with the degree of cognitive deficit and AD neuropathology. These findings define an OPN-dependent pathway to disease driven by a distinct microglial subset, and identify OPN as a novel therapeutic target for potentially effective immunotherapy to treat AD.

Original languageAmerican English
Article numbere2218915120
JournalProceedings of the National Academy of Sciences of the United States of America
Volume120
Issue number6
DOIs
StatePublished - 7 Feb 2023

Bibliographical note

Publisher Copyright:
Copyright © 2023 the Author(s). Published by PNAS.

Keywords

  • Alzheimer’s disease
  • Osteopontin
  • integrins
  • microglia
  • neuroinflammation

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