Phosphoproteomics identifies microglial Siglec‐F inflammatory response during neurodegeneration
Author(s)Morshed, Nader; Ralvenius, William; Nott, Alexander; Watson, Lauren Ashley; Rodriguez, Felicia H; Akay, Leyla Anne; Joughin, Brian Alan; Pao, Ping-Chieh; Penney, Jay; LaRocque, Lauren; Mastroeni, Diego; Tsai, Li‐Huei; White, Forest M.; ... Show more Show less
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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.
DepartmentMassachusetts Institute of Technology. Department of Biological Engineering; Picower Institute for Learning and Memory; Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences; Koch Institute for Integrative Cancer Research at MIT
Molecular Systems Biology
Morshed, Nader et al. "Phosphoproteomics identifies microglial Siglec‐F inflammatory response during neurodegeneration." Molecular Systems Biology 16, 12 (December 2020): e9819 ©2020 The Authors
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