Phosphoproteomics identifies microglial Siglec‐F inflammatory response during neurodegeneration. Issue 12 (8th December 2020)

• Record Type: Journal Article
• Authors: Morshed, Nader; Ralvenius, William T; Nott, Alexi; Watson, L Ashley; Rodriguez, Felicia H; Akay, Leyla A; Joughin, Brian A; Pao, Ping‐Chieh; Penney, Jay; LaRocque, Lauren; Mastroeni, Diego; Tsai, Li‐Huei; White, Forest M
• Is Part Of: Molecular systems biology. Volume 16:Issue 12(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-08
• Subjects: Alzheimer's disease -- microglia -- phosphoproteomics -- Siglec‐8 -- Siglec‐F; Molecular biology -- Periodicals; Systems biology -- Periodicals; 572.8
• DOI: 10.15252/msb.20209819
• Languages: English
• ISSNs: 1744-4292

Abstract

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. SYNOPSIS: Phosphoproteomics analyses of CK‐p25, 5XFAD, and Tau P301S mouse models of neurodegeneration identify dysregulated signaling networks associated with Alzheimer's disease pathologies. Phosphorylation sites on Siglec‐F and Inpp5d are upregulated across three mouse models of Alzheimer's disease. Expression of Siglec‐F and its human paralog Siglec‐8 is increased in reactive microglia. Siglec‐F and Siglec‐8 can be upregulated by interferon gamma in BV‐2 cell line and human stem cell‐derived microglia models. Overexpression of Siglec‐F and Siglec‐8 in BV‐2 cells drives an endocytic and pyroptotic inflammatory response. Abstract : Phosphoproteomics analyses of CK‐p25, 5XFAD, and Tau P301S mouse models of neurodegeneration identify dysregulated signaling networks associated with Alzheimer's disease pathologies.