NFκB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer's disease
Abnormal NFκB activation has been implicated in Alzheimer's disease (AD). However, the signaling pathways governing NFκB regulation and function in the brain are poorly understood. We identify complement protein C3 as an astroglial target of NFκB and show that C3 release acts through neuronal C...
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| Veröffentlicht in: | Neuron (Cambridge, Mass.) Mass.), 2015-01, Vol.85 (1), p.101-115 |
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| creator | Lian, Hong Yang, Li Cole, Allysa Sun, Lu Chiang, Angie C-A Fowler, Stephanie W Shim, David J Rodriguez-Rivera, Jennifer Taglialatela, Giulio Jankowsky, Joanna L Lu, Hui-Chen Zheng, Hui |
| description | Abnormal NFκB activation has been implicated in Alzheimer's disease (AD). However, the signaling pathways governing NFκB regulation and function in the brain are poorly understood. We identify complement protein C3 as an astroglial target of NFκB and show that C3 release acts through neuronal C3aR to disrupt dendritic morphology and network function. Exposure to Aβ activates astroglial NFκB and C3 release, consistent with the high levels of C3 expression in brain tissue from AD patients and APP transgenic mice, where C3aR antagonist treatment rescues cognitive impairment. Therefore, dysregulation of neuron-glia interaction through NFκB/C3/C3aR signaling may contribute to synaptic dysfunction in AD, and C3aR antagonists may be therapeutically beneficial. |
| doi_str_mv | 10.1016/j.neuron.2014.11.018 |
| format | Article |
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However, the signaling pathways governing NFκB regulation and function in the brain are poorly understood. We identify complement protein C3 as an astroglial target of NFκB and show that C3 release acts through neuronal C3aR to disrupt dendritic morphology and network function. Exposure to Aβ activates astroglial NFκB and C3 release, consistent with the high levels of C3 expression in brain tissue from AD patients and APP transgenic mice, where C3aR antagonist treatment rescues cognitive impairment. Therefore, dysregulation of neuron-glia interaction through NFκB/C3/C3aR signaling may contribute to synaptic dysfunction in AD, and C3aR antagonists may be therapeutically beneficial.</description><identifier>ISSN: 0896-6273</identifier><identifier>EISSN: 1097-4199</identifier><identifier>DOI: 10.1016/j.neuron.2014.11.018</identifier><identifier>PMID: 25533482</identifier><language>eng</language><publisher>United States: Elsevier Limited</publisher><subject>Alzheimer Disease - metabolism ; Alzheimer Disease - pathology ; Alzheimer's disease ; Amyloid beta-Peptides - metabolism ; Amyloid beta-Protein Precursor - genetics ; Animals ; Antagonists ; Astrocytes - metabolism ; Binding sites ; Brain - metabolism ; Cognitive ability ; Complement C3 - metabolism ; Complement component C3 ; Complement component C3a ; Complement receptors ; Homeostasis ; Humans ; Mice ; Mice, Transgenic ; Microscopy, Confocal ; Morphology ; Neuronal-glial interactions ; Neurons ; Neurons - metabolism ; Neurons - pathology ; NF-kappa B - metabolism ; NF-κB protein ; Proteins ; Receptors, Complement - antagonists & inhibitors ; Receptors, Complement - metabolism ; Signal Transduction ; Transgenic mice ; Tumor necrosis factor-TNF</subject><ispartof>Neuron (Cambridge, Mass.), 2015-01, Vol.85 (1), p.101-115</ispartof><rights>Copyright © 2015 Elsevier Inc. All rights reserved.</rights><rights>Copyright Elsevier Limited Jan 7, 2015</rights><rights>2014 Elsevier Inc. All rights reserved 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c539t-979905a4584aeebcf7648ef080014bfb4d2e4a2662ea11ca0b1bd40ced82140d3</citedby><cites>FETCH-LOGICAL-c539t-979905a4584aeebcf7648ef080014bfb4d2e4a2662ea11ca0b1bd40ced82140d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25533482$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lian, Hong</creatorcontrib><creatorcontrib>Yang, Li</creatorcontrib><creatorcontrib>Cole, Allysa</creatorcontrib><creatorcontrib>Sun, Lu</creatorcontrib><creatorcontrib>Chiang, Angie C-A</creatorcontrib><creatorcontrib>Fowler, Stephanie W</creatorcontrib><creatorcontrib>Shim, David J</creatorcontrib><creatorcontrib>Rodriguez-Rivera, Jennifer</creatorcontrib><creatorcontrib>Taglialatela, Giulio</creatorcontrib><creatorcontrib>Jankowsky, Joanna L</creatorcontrib><creatorcontrib>Lu, Hui-Chen</creatorcontrib><creatorcontrib>Zheng, Hui</creatorcontrib><title>NFκB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer's disease</title><title>Neuron (Cambridge, Mass.)</title><addtitle>Neuron</addtitle><description>Abnormal NFκB activation has been implicated in Alzheimer's disease (AD). However, the signaling pathways governing NFκB regulation and function in the brain are poorly understood. We identify complement protein C3 as an astroglial target of NFκB and show that C3 release acts through neuronal C3aR to disrupt dendritic morphology and network function. Exposure to Aβ activates astroglial NFκB and C3 release, consistent with the high levels of C3 expression in brain tissue from AD patients and APP transgenic mice, where C3aR antagonist treatment rescues cognitive impairment. Therefore, dysregulation of neuron-glia interaction through NFκB/C3/C3aR signaling may contribute to synaptic dysfunction in AD, and C3aR antagonists may be therapeutically beneficial.</description><subject>Alzheimer Disease - metabolism</subject><subject>Alzheimer Disease - pathology</subject><subject>Alzheimer's disease</subject><subject>Amyloid beta-Peptides - metabolism</subject><subject>Amyloid beta-Protein Precursor - genetics</subject><subject>Animals</subject><subject>Antagonists</subject><subject>Astrocytes - metabolism</subject><subject>Binding sites</subject><subject>Brain - metabolism</subject><subject>Cognitive ability</subject><subject>Complement C3 - metabolism</subject><subject>Complement component C3</subject><subject>Complement component C3a</subject><subject>Complement receptors</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Microscopy, Confocal</subject><subject>Morphology</subject><subject>Neuronal-glial interactions</subject><subject>Neurons</subject><subject>Neurons - metabolism</subject><subject>Neurons - pathology</subject><subject>NF-kappa B - metabolism</subject><subject>NF-κB protein</subject><subject>Proteins</subject><subject>Receptors, Complement - antagonists & inhibitors</subject><subject>Receptors, Complement - metabolism</subject><subject>Signal Transduction</subject><subject>Transgenic mice</subject><subject>Tumor necrosis factor-TNF</subject><issn>0896-6273</issn><issn>1097-4199</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNksFu1DAQhi0EokvhDRCyxAEuWTy2k9gXpLKigFTBBc6W40x2s3LixU5alTNPxUPwTHibUgEnTpblz59nxj8hT4GtgUH1ar8ecY5hXHMGcg2wZqDukRUwXRcStL5PVkzpqqh4LU7Io5T2LIOlhofkhJelEFLxFfn-8fznjzeFdVN_aSdsqU1TDFvfW08jerQJaeioC8PB44DjRDfiZhfD0CdMdCki00OIh13wYXtN7djSbh6zM4xZmILrb9xX_bSjZ_7bDvsB44tE26zILzwmDzrrEz65XU_Jl_O3nzfvi4tP7z5szi4KVwo9FbrWmpVWlkpaxMZ1dSUVdkwdG2u6RrYcpeVVxdECOMsaaFrJHLaKg2StOCWvF-9hbgZsXW4nWm8OsR9svDbB9ubvk7HfmW24NJIrnQebBS9vBTF8nTFNJg_Bofd2xDAnA5WsGdMV8P9BSy5YWUFGn_-D7sMc80wXqhZMKZEpuVAuhpQidnd1AzPHRJi9WT7DHBNhAExORL727M-e7y79joD4BQkTt_s</recordid><startdate>20150107</startdate><enddate>20150107</enddate><creator>Lian, Hong</creator><creator>Yang, Li</creator><creator>Cole, Allysa</creator><creator>Sun, Lu</creator><creator>Chiang, Angie C-A</creator><creator>Fowler, Stephanie W</creator><creator>Shim, David J</creator><creator>Rodriguez-Rivera, Jennifer</creator><creator>Taglialatela, Giulio</creator><creator>Jankowsky, Joanna L</creator><creator>Lu, Hui-Chen</creator><creator>Zheng, Hui</creator><general>Elsevier Limited</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>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20150107</creationdate><title>NFκB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer's disease</title><author>Lian, Hong ; Yang, Li ; Cole, Allysa ; Sun, Lu ; Chiang, Angie C-A ; Fowler, Stephanie W ; Shim, David J ; Rodriguez-Rivera, Jennifer ; Taglialatela, Giulio ; Jankowsky, Joanna L ; Lu, Hui-Chen ; Zheng, Hui</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c539t-979905a4584aeebcf7648ef080014bfb4d2e4a2662ea11ca0b1bd40ced82140d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Alzheimer Disease - metabolism</topic><topic>Alzheimer Disease - pathology</topic><topic>Alzheimer's disease</topic><topic>Amyloid beta-Peptides - metabolism</topic><topic>Amyloid beta-Protein Precursor - genetics</topic><topic>Animals</topic><topic>Antagonists</topic><topic>Astrocytes - metabolism</topic><topic>Binding sites</topic><topic>Brain - metabolism</topic><topic>Cognitive ability</topic><topic>Complement C3 - metabolism</topic><topic>Complement component C3</topic><topic>Complement component C3a</topic><topic>Complement receptors</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Microscopy, Confocal</topic><topic>Morphology</topic><topic>Neuronal-glial interactions</topic><topic>Neurons</topic><topic>Neurons - metabolism</topic><topic>Neurons - pathology</topic><topic>NF-kappa B - metabolism</topic><topic>NF-κB protein</topic><topic>Proteins</topic><topic>Receptors, Complement - antagonists & inhibitors</topic><topic>Receptors, Complement - metabolism</topic><topic>Signal Transduction</topic><topic>Transgenic mice</topic><topic>Tumor necrosis factor-TNF</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lian, Hong</creatorcontrib><creatorcontrib>Yang, Li</creatorcontrib><creatorcontrib>Cole, Allysa</creatorcontrib><creatorcontrib>Sun, Lu</creatorcontrib><creatorcontrib>Chiang, Angie C-A</creatorcontrib><creatorcontrib>Fowler, Stephanie W</creatorcontrib><creatorcontrib>Shim, David J</creatorcontrib><creatorcontrib>Rodriguez-Rivera, Jennifer</creatorcontrib><creatorcontrib>Taglialatela, Giulio</creatorcontrib><creatorcontrib>Jankowsky, Joanna L</creatorcontrib><creatorcontrib>Lu, Hui-Chen</creatorcontrib><creatorcontrib>Zheng, Hui</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Neuron (Cambridge, Mass.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lian, Hong</au><au>Yang, Li</au><au>Cole, Allysa</au><au>Sun, Lu</au><au>Chiang, Angie C-A</au><au>Fowler, Stephanie W</au><au>Shim, David J</au><au>Rodriguez-Rivera, Jennifer</au><au>Taglialatela, Giulio</au><au>Jankowsky, Joanna L</au><au>Lu, Hui-Chen</au><au>Zheng, Hui</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>NFκB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer's disease</atitle><jtitle>Neuron (Cambridge, Mass.)</jtitle><addtitle>Neuron</addtitle><date>2015-01-07</date><risdate>2015</risdate><volume>85</volume><issue>1</issue><spage>101</spage><epage>115</epage><pages>101-115</pages><issn>0896-6273</issn><eissn>1097-4199</eissn><abstract>Abnormal NFκB activation has been implicated in Alzheimer's disease (AD). However, the signaling pathways governing NFκB regulation and function in the brain are poorly understood. We identify complement protein C3 as an astroglial target of NFκB and show that C3 release acts through neuronal C3aR to disrupt dendritic morphology and network function. Exposure to Aβ activates astroglial NFκB and C3 release, consistent with the high levels of C3 expression in brain tissue from AD patients and APP transgenic mice, where C3aR antagonist treatment rescues cognitive impairment. Therefore, dysregulation of neuron-glia interaction through NFκB/C3/C3aR signaling may contribute to synaptic dysfunction in AD, and C3aR antagonists may be therapeutically beneficial.</abstract><cop>United States</cop><pub>Elsevier Limited</pub><pmid>25533482</pmid><doi>10.1016/j.neuron.2014.11.018</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Cell Press Free Archives; Elsevier ScienceDirect Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Alzheimer Disease - metabolism Alzheimer Disease - pathology Alzheimer's disease Amyloid beta-Peptides - metabolism Amyloid beta-Protein Precursor - genetics Animals Antagonists Astrocytes - metabolism Binding sites Brain - metabolism Cognitive ability Complement C3 - metabolism Complement component C3 Complement component C3a Complement receptors Homeostasis Humans Mice Mice, Transgenic Microscopy, Confocal Morphology Neuronal-glial interactions Neurons Neurons - metabolism Neurons - pathology NF-kappa B - metabolism NF-κB protein Proteins Receptors, Complement - antagonists & inhibitors Receptors, Complement - metabolism Signal Transduction Transgenic mice Tumor necrosis factor-TNF |
| title | NFκB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer's disease |
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