@article{15368e56860f49d6a1e82c80d72d7e4c,
title = "Phosphoproteomics identifies microglial Siglec-F inflammatory response during neurodegeneration",
abstract = "Alzheimer{\textquoteright}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.",
keywords = "Alzheimer's disease, Siglec-8, Siglec-F, microglia, phosphoproteomics",
author = "Nader Morshed and Ralvenius, {William T.} and Alexi Nott and Watson, {L. Ashley} and Rodriguez, {Felicia H.} and Akay, {Leyla A.} and Joughin, {Brian A.} and Pao, {Ping Chieh} and Jay Penney and Lauren LaRocque and Diego Mastroeni and Tsai, {Li Huei} and White, {Forest M.}",
note = "Funding Information: We thank members of the White and Tsai laboratories for numerous discussions and feedback. We also thank C. Whittaker for help with RNA‐seq analysis, J. Cheah for help with BV‐2 assay development and screening, and R. Ahn for discussions on signal transduction mechanisms. N.M. was partially supported by the NIH Biotechnology Training Grant T32GM008334. D.M. was supported by NIRG‐15‐321390, and Arizona Alzheimer{\textquoteright}s Consortium. This work was supported by the Center for Precision Cancer Medicine at MIT, NIH grants U54‐CA210180, R37‐NS051874, RF1‐AG054321, a grant from the Simons Center for the Social Brain, the Glenn Foundation and NDC Belfer (The Neurodegeneration Consortium, The Robert A. and Renee E. Belfer Family Foundation, and the Oskar Fisher Project) to L.‐H.T. Funding Information: We thank members of the White and Tsai laboratories for numerous discussions and feedback. We also thank C. Whittaker for help with RNA-seq analysis, J. Cheah for help with BV-2 assay development and screening, and R. Ahn for discussions on signal transduction mechanisms. N.M. was partially supported by the NIH Biotechnology Training Grant T32GM008334. D.M. was supported by NIRG-15-321390, and Arizona Alzheimer?s Consortium. This work was?supported by the Center for Precision Cancer Medicine at MIT, NIH grants U54-CA210180, R37-NS051874, RF1-AG054321, a grant from the Simons Center for the Social Brain,?the Glenn Foundation and?NDC Belfer (The Neurodegeneration Consortium, The Robert A. and Renee E. Belfer Family Foundation,?and the Oskar Fisher Project) to?L.-H.T. Publisher Copyright: {\textcopyright} 2020 The Authors. Published under the terms of the CC BY 4.0 license",
year = "2020",
month = dec,
doi = "10.15252/msb.20209819",
language = "English (US)",
volume = "16",
journal = "Molecular Systems Biology",
issn = "1744-4292",
publisher = "Nature Publishing Group",
number = "12",
}