Phosphoproteomics identifies microglial Siglec-F inflammatory response during neurodegeneration

Nader Morshed, William T. Ralvenius, Alexi Nott, L. Ashley Watson, Felicia H. Rodriguez, Leyla A. Akay, Brian A. Joughin, Ping Chieh Pao, Jay Penney, Lauren LaRocque, Diego Mastroeni, Li Huei Tsai, Forest M. White

Research output: Contribution to journalArticlepeer-review

Abstract

Alzheimer’s disease (AD) is characterized by the appearance of amyloid-β plaques, neurofibrillary tangles, and inflammation in brain regions involved in memory. Using mass spectrometry, we have quantified the phosphoproteome of the CK-p25, 5XFAD, and Tau P301S mouse models of neurodegeneration. We identified a shared response involving Siglec-F which was upregulated on a subset of reactive microglia. The human paralog Siglec-8 was also upregulated on microglia in AD. Siglec-F and Siglec-8 were upregulated following microglial activation with interferon gamma (IFNγ) in BV-2 cell line and human stem cell-derived microglia models. Siglec-F overexpression activates an endocytic and pyroptotic inflammatory response in BV-2 cells, dependent on its sialic acid substrates and immunoreceptor tyrosine-based inhibition motif (ITIM) phosphorylation sites. Related human Siglecs induced a similar response in BV-2 cells. Collectively, our results point to an important role for mouse Siglec-F and human Siglec-8 in regulating microglial activation during neurodegeneration.

Original languageEnglish (US)
Article numbere9819
JournalMolecular Systems Biology
Volume16
Issue number12
DOIs
StatePublished - Dec 2020

Keywords

  • Alzheimer's disease
  • Siglec-8
  • Siglec-F
  • microglia
  • phosphoproteomics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)
  • Applied Mathematics

Fingerprint Dive into the research topics of 'Phosphoproteomics identifies microglial Siglec-F inflammatory response during neurodegeneration'. Together they form a unique fingerprint.

Cite this