Phosphoproteomics identifies microglial Siglec-F inflammatory response during neurodegeneration.

TitlePhosphoproteomics identifies microglial Siglec-F inflammatory response during neurodegeneration.
Publication TypeJournal Article
Year of Publication2020
AuthorsMorshed N, Ralvenius WT, Nott A, L Watson A, Rodriguez FH, Akay LA, Joughin BA, Pao P-C, Penney J, LaRocque L, Mastroeni D, Tsai L-H, White FM
JournalMol Syst Biol
Date Published2020 12

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.

Alternate JournalMol Syst Biol
PubMed ID33289969
PubMed Central IDPMC7722784
Grant ListR37 NS051874 / NS / NINDS NIH HHS / United States
RF1 AG054321 / AG / NIA NIH HHS / United States
T32 GM008334 / GM / NIGMS NIH HHS / United States
U54 CA210180 / CA / NCI NIH HHS / United States