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

doi:10.15252/msb.20209819

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

ASU-Banner Neurodegenerative Disease Research Center (NDRC)

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

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 language	English (US)
Article number	e9819
Journal	Molecular Systems Biology
Volume	16
Issue number	12
DOIs	https://doi.org/10.15252/msb.20209819
State	Published - Dec 2020

Keywords

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

ASJC Scopus subject areas

General Agricultural and Biological Sciences
Information Systems
Applied Mathematics
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology
Computational Theory and Mathematics

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10.15252/msb.20209819

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Morshed, N., Ralvenius, W. T., Nott, A., Watson, L. A., Rodriguez, F. H., Akay, L. A., Joughin, B. A., Pao, P. C., Penney, J., LaRocque, L., Mastroeni, D., Tsai, L. H., & White, F. M. (2020). Phosphoproteomics identifies microglial Siglec-F inflammatory response during neurodegeneration. Molecular Systems Biology, 16(12), Article e9819. https://doi.org/10.15252/msb.20209819

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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.}",

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doi = "10.15252/msb.20209819",

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AU - Ralvenius, William T.

AU - Nott, Alexi

AU - Watson, L. Ashley

AU - Rodriguez, Felicia H.

AU - Akay, Leyla A.

AU - Joughin, Brian A.

AU - Pao, Ping Chieh

AU - Penney, Jay

AU - LaRocque, Lauren

AU - Mastroeni, Diego

AU - Tsai, Li Huei

AU - White, Forest M.

PY - 2020/12

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N2 - 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.

AB - 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.

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Phosphoproteomics identifies microglial Siglec-F inflammatory response during neurodegeneration

Abstract

Keywords

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