Phosphoproteomics identifies microglial Siglec‐F inflammatory response during neurodegeneration
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 neurodegenerat...
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| Format: | Article |
| Language: | English |
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Springer Nature
2020-12-01
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| Series: | Molecular Systems Biology |
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| Online Access: | https://doi.org/10.15252/msb.20209819 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Nader Morshed |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-7b9677d83e734c9bb4414abb7d975e62 |
| institution | DOAJ |
| issn | 1744-4292 |
| language | English |
| publishDate | 2020-12-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj-art-7b9677d83e734c9bb4414abb7d975e622025-08-20T03:06:10ZengSpringer NatureMolecular Systems Biology1744-42922020-12-01161212710.15252/msb.20209819Phosphoproteomics identifies microglial Siglec‐F inflammatory response during neurodegenerationNader Morshed0William T Ralvenius1Alexi Nott2L Ashley Watson3Felicia H Rodriguez4Leyla A Akay5Brian A Joughin6Ping‐Chieh Pao7Jay Penney8Lauren LaRocque9Diego Mastroeni10Li‐Huei Tsai11Forest M White12Department of Biological Engineering, Massachusetts Institute of TechnologyPicower Institute for Learning and Memory, Massachusetts Institute of TechnologyPicower Institute for Learning and Memory, Massachusetts Institute of TechnologyPicower Institute for Learning and Memory, Massachusetts Institute of TechnologyDepartment of Chemical and Materials Engineering, New Mexico State UniversityPicower Institute for Learning and Memory, Massachusetts Institute of TechnologyDepartment of Biological Engineering, Massachusetts Institute of TechnologyPicower Institute for Learning and Memory, Massachusetts Institute of TechnologyPicower Institute for Learning and Memory, Massachusetts Institute of TechnologyDepartment of Biological Engineering, Massachusetts Institute of TechnologyASU‐Banner Neurodegenerative Disease Research CenterPicower Institute for Learning and Memory, Massachusetts Institute of TechnologyDepartment of Biological Engineering, Massachusetts Institute of TechnologyAbstract 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.https://doi.org/10.15252/msb.20209819Alzheimer's diseasemicrogliaphosphoproteomicsSiglec‐8Siglec‐F |
| spellingShingle | 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 Phosphoproteomics identifies microglial Siglec‐F inflammatory response during neurodegeneration Molecular Systems Biology Alzheimer's disease microglia phosphoproteomics Siglec‐8 Siglec‐F |
| title | Phosphoproteomics identifies microglial Siglec‐F inflammatory response during neurodegeneration |
| title_full | Phosphoproteomics identifies microglial Siglec‐F inflammatory response during neurodegeneration |
| title_fullStr | Phosphoproteomics identifies microglial Siglec‐F inflammatory response during neurodegeneration |
| title_full_unstemmed | Phosphoproteomics identifies microglial Siglec‐F inflammatory response during neurodegeneration |
| title_short | Phosphoproteomics identifies microglial Siglec‐F inflammatory response during neurodegeneration |
| title_sort | phosphoproteomics identifies microglial siglec f inflammatory response during neurodegeneration |
| topic | Alzheimer's disease microglia phosphoproteomics Siglec‐8 Siglec‐F |
| url | https://doi.org/10.15252/msb.20209819 |
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