Extracellular signal‐regulated kinase regulates microglial immune responses in Alzheimer’s disease
The importance of mitogen‐activated protein kinase (MAPK) pathway signaling in regulating microglia‐mediated neuroinflammation in Alzheimer's disease (AD) remains unclear. We examined the role of MAPK signaling in microglia using a preclinical model of AD pathology and quantitative proteomics s...
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| Veröffentlicht in: | Journal of neuroscience research 2021-06, Vol.99 (6), p.1704-1721 |
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| creator | Chen, Michael J. Ramesha, Supriya Weinstock, Laura D. Gao, Tianwen Ping, Lingyan Xiao, Hailian Dammer, Eric B. Duong, Duc D. Levey, Allan I. Lah, James J. Seyfried, Nicholas T. Wood, Levi B. Rangaraju, Srikant |
| description | The importance of mitogen‐activated protein kinase (MAPK) pathway signaling in regulating microglia‐mediated neuroinflammation in Alzheimer's disease (AD) remains unclear. We examined the role of MAPK signaling in microglia using a preclinical model of AD pathology and quantitative proteomics studies of postmortem human brains. In multiplex immunoassay analyses of MAPK phosphoproteins in acutely isolated microglia and brain tissue from 5xFAD mice, we found phosphorylated extracellular signal‐regulated kinase (ERK) was the most strongly upregulated phosphoprotein within the MAPK pathway in acutely isolated microglia, but not whole‐brain tissue from 5xFAD mice. The importance of ERK signaling in primary microglia cultures was next investigated using transcriptomic profiling and functional assays of amyloid‐β and neuronal phagocytosis, which confirmed that ERK is a critical regulator of IFNγ‐mediated pro‐inflammatory activation of microglia, although it was also partly important for constitutive microglial functions. Phospho‐ERK was an upstream regulator of disease‐associated microglial gene expression (Trem2, Tyrobp), as well as several human AD risk genes (Bin1, Cd33, Trem2, Cnn2), indicative of the importance of microglial ERK signaling in AD pathology. Quantitative proteomic analyses of postmortem human brain showed that ERK1 and ERK2 were the only MAPK proteins with increased protein expression and positive associations with neuropathological grade. In a human brain phosphoproteomic study, we found evidence for increased flux through the ERK signaling pathway in AD. Overall, our analyses strongly suggest that ERK phosphorylation, particularly in microglia in mouse models, is a regulator of pro‐inflammatory immune responses in AD pathogenesis.
We demonstrate a critical role for ERK signaling in microglia in Alzheimer’s disease using a preclinical model of Alzheimer’s disease pathology and quantitative studies of postmortem human brains. |
| doi_str_mv | 10.1002/jnr.24829 |
| format | Article |
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We demonstrate a critical role for ERK signaling in microglia in Alzheimer’s disease using a preclinical model of Alzheimer’s disease pathology and quantitative studies of postmortem human brains.</description><identifier>ISSN: 0360-4012</identifier><identifier>EISSN: 1097-4547</identifier><identifier>DOI: 10.1002/jnr.24829</identifier><identifier>PMID: 33729626</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>Alzheimer Disease - genetics ; Alzheimer Disease - immunology ; Alzheimer's disease ; Amyloid ; Amyloid beta-Peptides - metabolism ; Animal models ; Animal tissues ; Animals ; Autopsy ; Brain ; ERK ; Extracellular signal-regulated kinase ; Female ; Gene Expression ; Immune response ; Immunoassay ; Inflammation ; Kinases ; Male ; MAP kinase ; MAP Kinase Signaling System - genetics ; Mice ; Microglia ; Microglia - immunology ; Neurodegenerative diseases ; neuroinflammation ; Pathogenesis ; Pathology ; Phagocytosis ; Phosphoproteins ; Phosphorylation ; Primary Cell Culture ; Protein kinase ; Proteins ; Proteomics ; RRID:AB_331646 ; RRID:AB_354872 ; RRID:AB_394489 ; RRID:AB_396772 ; RRID:CVCL_0470 ; RRID:IMSR_JAX:000664 ; RRID:MMRRC_034840‐JAX ; RRID:SCR_002798 ; RRID:SCR_002865 ; RRID:SCR_003420 ; RRID:SCR_017386 ; Signal transduction ; Signaling ; Transcriptome ; γ-Interferon</subject><ispartof>Journal of neuroscience research, 2021-06, Vol.99 (6), p.1704-1721</ispartof><rights>2021 Wiley Periodicals LLC</rights><rights>2021 Wiley Periodicals LLC.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5099-6beabf4967938986826ac99a8493f9e25f774e467d5173b9a24702a33d88238a3</citedby><cites>FETCH-LOGICAL-c5099-6beabf4967938986826ac99a8493f9e25f774e467d5173b9a24702a33d88238a3</cites><orcidid>0000-0003-2765-1500</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjnr.24829$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjnr.24829$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,776,780,881,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33729626$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Michael J.</creatorcontrib><creatorcontrib>Ramesha, Supriya</creatorcontrib><creatorcontrib>Weinstock, Laura D.</creatorcontrib><creatorcontrib>Gao, Tianwen</creatorcontrib><creatorcontrib>Ping, Lingyan</creatorcontrib><creatorcontrib>Xiao, Hailian</creatorcontrib><creatorcontrib>Dammer, Eric B.</creatorcontrib><creatorcontrib>Duong, Duc D.</creatorcontrib><creatorcontrib>Levey, Allan I.</creatorcontrib><creatorcontrib>Lah, James J.</creatorcontrib><creatorcontrib>Seyfried, Nicholas T.</creatorcontrib><creatorcontrib>Wood, Levi B.</creatorcontrib><creatorcontrib>Rangaraju, Srikant</creatorcontrib><title>Extracellular signal‐regulated kinase regulates microglial immune responses in Alzheimer’s disease</title><title>Journal of neuroscience research</title><addtitle>J Neurosci Res</addtitle><description>The importance of mitogen‐activated protein kinase (MAPK) pathway signaling in regulating microglia‐mediated neuroinflammation in Alzheimer's disease (AD) remains unclear. We examined the role of MAPK signaling in microglia using a preclinical model of AD pathology and quantitative proteomics studies of postmortem human brains. In multiplex immunoassay analyses of MAPK phosphoproteins in acutely isolated microglia and brain tissue from 5xFAD mice, we found phosphorylated extracellular signal‐regulated kinase (ERK) was the most strongly upregulated phosphoprotein within the MAPK pathway in acutely isolated microglia, but not whole‐brain tissue from 5xFAD mice. The importance of ERK signaling in primary microglia cultures was next investigated using transcriptomic profiling and functional assays of amyloid‐β and neuronal phagocytosis, which confirmed that ERK is a critical regulator of IFNγ‐mediated pro‐inflammatory activation of microglia, although it was also partly important for constitutive microglial functions. Phospho‐ERK was an upstream regulator of disease‐associated microglial gene expression (Trem2, Tyrobp), as well as several human AD risk genes (Bin1, Cd33, Trem2, Cnn2), indicative of the importance of microglial ERK signaling in AD pathology. Quantitative proteomic analyses of postmortem human brain showed that ERK1 and ERK2 were the only MAPK proteins with increased protein expression and positive associations with neuropathological grade. In a human brain phosphoproteomic study, we found evidence for increased flux through the ERK signaling pathway in AD. Overall, our analyses strongly suggest that ERK phosphorylation, particularly in microglia in mouse models, is a regulator of pro‐inflammatory immune responses in AD pathogenesis.
We demonstrate a critical role for ERK signaling in microglia in Alzheimer’s disease using a preclinical model of Alzheimer’s disease pathology and quantitative studies of postmortem human brains.</description><subject>Alzheimer Disease - genetics</subject><subject>Alzheimer Disease - immunology</subject><subject>Alzheimer's disease</subject><subject>Amyloid</subject><subject>Amyloid beta-Peptides - metabolism</subject><subject>Animal models</subject><subject>Animal tissues</subject><subject>Animals</subject><subject>Autopsy</subject><subject>Brain</subject><subject>ERK</subject><subject>Extracellular signal-regulated kinase</subject><subject>Female</subject><subject>Gene Expression</subject><subject>Immune response</subject><subject>Immunoassay</subject><subject>Inflammation</subject><subject>Kinases</subject><subject>Male</subject><subject>MAP kinase</subject><subject>MAP Kinase Signaling System - genetics</subject><subject>Mice</subject><subject>Microglia</subject><subject>Microglia - immunology</subject><subject>Neurodegenerative diseases</subject><subject>neuroinflammation</subject><subject>Pathogenesis</subject><subject>Pathology</subject><subject>Phagocytosis</subject><subject>Phosphoproteins</subject><subject>Phosphorylation</subject><subject>Primary Cell Culture</subject><subject>Protein kinase</subject><subject>Proteins</subject><subject>Proteomics</subject><subject>RRID:AB_331646</subject><subject>RRID:AB_354872</subject><subject>RRID:AB_394489</subject><subject>RRID:AB_396772</subject><subject>RRID:CVCL_0470</subject><subject>RRID:IMSR_JAX:000664</subject><subject>RRID:MMRRC_034840‐JAX</subject><subject>RRID:SCR_002798</subject><subject>RRID:SCR_002865</subject><subject>RRID:SCR_003420</subject><subject>RRID:SCR_017386</subject><subject>Signal transduction</subject><subject>Signaling</subject><subject>Transcriptome</subject><subject>γ-Interferon</subject><issn>0360-4012</issn><issn>1097-4547</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kU1uFDEQhS1ERIbAggugltiERSf-bbs2SFEU_hSBhGBtebqrJx7c7sGeTgirHIEt18tJ8GSSCJBYWar6_PTqPUKeMXrAKOWHy5gOuDQcHpAZo6BrqaR-SGZUNLSWlPFd8jjnJaUUQIlHZFcIzaHhzYz0J9_XybUYwhRcqrJfRBeur34mXJTBGrvqq48uY3U3yNXg2zQugneh8sMwxc0ur8aYy87H6ij8OEM_YLq--pWrzmcs35-Qnd6FjE9v3z3y5fXJ5-O39enHN--Oj07rVhVvdTNHN-8lNBqEAdMY3rgWwBkJogfkqtdaomx0p5gWc3BcasqdEJ0xXBgn9sirre5qmg_YtRjLdcGukh9curSj8_bvTfRndjGeWwMMFIgisH8rkMZvE-a1HXzexOMijlO2XFHOGTdKFfTFP-hynFKJb0MxoEJTxQr1ckuV0HJO2N-bYdRu2rOlPXvTXmGf_-n-nryrqwCHW-DCB7z8v5J9_-HTVvI3w0anmA</recordid><startdate>202106</startdate><enddate>202106</enddate><creator>Chen, Michael J.</creator><creator>Ramesha, Supriya</creator><creator>Weinstock, Laura D.</creator><creator>Gao, Tianwen</creator><creator>Ping, Lingyan</creator><creator>Xiao, Hailian</creator><creator>Dammer, Eric B.</creator><creator>Duong, Duc D.</creator><creator>Levey, Allan I.</creator><creator>Lah, James J.</creator><creator>Seyfried, Nicholas T.</creator><creator>Wood, Levi B.</creator><creator>Rangaraju, Srikant</creator><general>Wiley Subscription Services, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-2765-1500</orcidid></search><sort><creationdate>202106</creationdate><title>Extracellular signal‐regulated kinase regulates microglial immune responses in Alzheimer’s disease</title><author>Chen, Michael J. ; Ramesha, Supriya ; Weinstock, Laura D. ; Gao, Tianwen ; Ping, Lingyan ; Xiao, Hailian ; Dammer, Eric B. ; Duong, Duc D. ; Levey, Allan I. ; Lah, James J. ; Seyfried, Nicholas T. ; Wood, Levi B. ; Rangaraju, Srikant</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5099-6beabf4967938986826ac99a8493f9e25f774e467d5173b9a24702a33d88238a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Alzheimer Disease - genetics</topic><topic>Alzheimer Disease - immunology</topic><topic>Alzheimer's disease</topic><topic>Amyloid</topic><topic>Amyloid beta-Peptides - metabolism</topic><topic>Animal models</topic><topic>Animal tissues</topic><topic>Animals</topic><topic>Autopsy</topic><topic>Brain</topic><topic>ERK</topic><topic>Extracellular signal-regulated kinase</topic><topic>Female</topic><topic>Gene Expression</topic><topic>Immune response</topic><topic>Immunoassay</topic><topic>Inflammation</topic><topic>Kinases</topic><topic>Male</topic><topic>MAP kinase</topic><topic>MAP Kinase Signaling System - genetics</topic><topic>Mice</topic><topic>Microglia</topic><topic>Microglia - immunology</topic><topic>Neurodegenerative diseases</topic><topic>neuroinflammation</topic><topic>Pathogenesis</topic><topic>Pathology</topic><topic>Phagocytosis</topic><topic>Phosphoproteins</topic><topic>Phosphorylation</topic><topic>Primary Cell Culture</topic><topic>Protein kinase</topic><topic>Proteins</topic><topic>Proteomics</topic><topic>RRID:AB_331646</topic><topic>RRID:AB_354872</topic><topic>RRID:AB_394489</topic><topic>RRID:AB_396772</topic><topic>RRID:CVCL_0470</topic><topic>RRID:IMSR_JAX:000664</topic><topic>RRID:MMRRC_034840‐JAX</topic><topic>RRID:SCR_002798</topic><topic>RRID:SCR_002865</topic><topic>RRID:SCR_003420</topic><topic>RRID:SCR_017386</topic><topic>Signal transduction</topic><topic>Signaling</topic><topic>Transcriptome</topic><topic>γ-Interferon</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Michael J.</creatorcontrib><creatorcontrib>Ramesha, Supriya</creatorcontrib><creatorcontrib>Weinstock, Laura D.</creatorcontrib><creatorcontrib>Gao, Tianwen</creatorcontrib><creatorcontrib>Ping, Lingyan</creatorcontrib><creatorcontrib>Xiao, Hailian</creatorcontrib><creatorcontrib>Dammer, Eric B.</creatorcontrib><creatorcontrib>Duong, Duc D.</creatorcontrib><creatorcontrib>Levey, Allan I.</creatorcontrib><creatorcontrib>Lah, James J.</creatorcontrib><creatorcontrib>Seyfried, Nicholas T.</creatorcontrib><creatorcontrib>Wood, Levi B.</creatorcontrib><creatorcontrib>Rangaraju, Srikant</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of neuroscience research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Michael J.</au><au>Ramesha, Supriya</au><au>Weinstock, Laura D.</au><au>Gao, Tianwen</au><au>Ping, Lingyan</au><au>Xiao, Hailian</au><au>Dammer, Eric B.</au><au>Duong, Duc D.</au><au>Levey, Allan I.</au><au>Lah, James J.</au><au>Seyfried, Nicholas T.</au><au>Wood, Levi B.</au><au>Rangaraju, Srikant</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Extracellular signal‐regulated kinase regulates microglial immune responses in Alzheimer’s disease</atitle><jtitle>Journal of neuroscience research</jtitle><addtitle>J Neurosci Res</addtitle><date>2021-06</date><risdate>2021</risdate><volume>99</volume><issue>6</issue><spage>1704</spage><epage>1721</epage><pages>1704-1721</pages><issn>0360-4012</issn><eissn>1097-4547</eissn><abstract>The importance of mitogen‐activated protein kinase (MAPK) pathway signaling in regulating microglia‐mediated neuroinflammation in Alzheimer's disease (AD) remains unclear. We examined the role of MAPK signaling in microglia using a preclinical model of AD pathology and quantitative proteomics studies of postmortem human brains. In multiplex immunoassay analyses of MAPK phosphoproteins in acutely isolated microglia and brain tissue from 5xFAD mice, we found phosphorylated extracellular signal‐regulated kinase (ERK) was the most strongly upregulated phosphoprotein within the MAPK pathway in acutely isolated microglia, but not whole‐brain tissue from 5xFAD mice. The importance of ERK signaling in primary microglia cultures was next investigated using transcriptomic profiling and functional assays of amyloid‐β and neuronal phagocytosis, which confirmed that ERK is a critical regulator of IFNγ‐mediated pro‐inflammatory activation of microglia, although it was also partly important for constitutive microglial functions. Phospho‐ERK was an upstream regulator of disease‐associated microglial gene expression (Trem2, Tyrobp), as well as several human AD risk genes (Bin1, Cd33, Trem2, Cnn2), indicative of the importance of microglial ERK signaling in AD pathology. Quantitative proteomic analyses of postmortem human brain showed that ERK1 and ERK2 were the only MAPK proteins with increased protein expression and positive associations with neuropathological grade. In a human brain phosphoproteomic study, we found evidence for increased flux through the ERK signaling pathway in AD. Overall, our analyses strongly suggest that ERK phosphorylation, particularly in microglia in mouse models, is a regulator of pro‐inflammatory immune responses in AD pathogenesis.
We demonstrate a critical role for ERK signaling in microglia in Alzheimer’s disease using a preclinical model of Alzheimer’s disease pathology and quantitative studies of postmortem human brains.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>33729626</pmid><doi>10.1002/jnr.24829</doi><tpages>0</tpages><orcidid>https://orcid.org/0000-0003-2765-1500</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| ispartof | Journal of neuroscience research, 2021-06, Vol.99 (6), p.1704-1721 |
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| language | eng |
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| subjects | Alzheimer Disease - genetics Alzheimer Disease - immunology Alzheimer's disease Amyloid Amyloid beta-Peptides - metabolism Animal models Animal tissues Animals Autopsy Brain ERK Extracellular signal-regulated kinase Female Gene Expression Immune response Immunoassay Inflammation Kinases Male MAP kinase MAP Kinase Signaling System - genetics Mice Microglia Microglia - immunology Neurodegenerative diseases neuroinflammation Pathogenesis Pathology Phagocytosis Phosphoproteins Phosphorylation Primary Cell Culture Protein kinase Proteins Proteomics RRID:AB_331646 RRID:AB_354872 RRID:AB_394489 RRID:AB_396772 RRID:CVCL_0470 RRID:IMSR_JAX:000664 RRID:MMRRC_034840‐JAX RRID:SCR_002798 RRID:SCR_002865 RRID:SCR_003420 RRID:SCR_017386 Signal transduction Signaling Transcriptome γ-Interferon |
| title | Extracellular signal‐regulated kinase regulates microglial immune responses in Alzheimer’s disease |
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