Blocking TGF-[beta]-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology
Alzheimer's disease is the most common dementia and is pathologically characterized by deposition of amyloid-[beta] peptide (A[beta]) into [beta]-amyloid plaques, neuronal injury and low-level, chronic activation of brain immunity. Transforming growth factor-[beta]s (TGF-[beta]s) are pleiotropi...
Gespeichert in:
| Veröffentlicht in: | Nature medicine 2008-06, Vol.14 (6), p.681-687 |
|---|---|
| Hauptverfasser: | , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 687 |
|---|---|
| container_issue | 6 |
| container_start_page | 681 |
| container_title | Nature medicine |
| container_volume | 14 |
| creator | Town, Terrence Laouar, Yasmina Pittenger, Christopher Mori, Takashi Szekely, Christine A Tan, Jun Duman, Ronald S Flavell, Richard A |
| description | Alzheimer's disease is the most common dementia and is pathologically characterized by deposition of amyloid-[beta] peptide (A[beta]) into [beta]-amyloid plaques, neuronal injury and low-level, chronic activation of brain immunity. Transforming growth factor-[beta]s (TGF-[beta]s) are pleiotropic cytokines that have key roles in immune cell activation, inflammation and repair after injury. We genetically interrupted TGF-[beta] and downstream Smad2/3 signaling (TGF-[beta]-Smad2/3) in innate immune cells by inducing expression of CD11c promoter-driven dominant-negative TGF-[beta] receptor type II in C57BL/6 mice (CD11c-DNR)3, crossed these mice with mice overexpressing mutant human amyloid precursor protein, the Tg2576 Alzheimer's disease mouse model, and evaluated Alzheimer's disease-like pathology. Aged double-transgenic mice showed complete mitigation of Tg2576-associated hyperactivity and partial mitigation of defective spatial working memory. Brain parenchymal and cerebrovascular [beta]-amyloid deposits and A[beta] abundance were markedly (up to 90%) attenuated in Tg2576-CD11c-DNR mice. This was associated with increased infiltration of A[beta]-containing peripheral macrophages around cerebral vessels and [beta]-amyloid plaques. In vitro, cultures of peripheral macrophages, but not microglia, from CD11c-DNR mice showed blockade of classical TGF-[beta]-activated Smad2/3 but also showed hyperactivation of alternative bone morphogenic protein-activated Smad1/5/8 signaling and increased A[beta] phagocytosis. Similar effects were noted after pharmacological inhibition of activin-like kinase-5, a type I TGF-[beta] receptor. Taken together, our results suggest that blockade of TGF-[beta]-Smad2/3 signaling in peripheral macrophages represents a new therapeutic target for Alzheimer's disease. [PUBLICATION ABSTRACT] |
| doi_str_mv | 10.1038/nm1781 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest</sourceid><recordid>TN_cdi_proquest_miscellaneous_20850245</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>20850245</sourcerecordid><originalsourceid>FETCH-LOGICAL-p585-9d973b40f5e48b8c66db6dbddbd64a76a97e7d4ec676ec032c36d0c123b37ed53</originalsourceid><addsrcrecordid>eNpdj01LAzEYhIMoWKv-hsWDt9hk87nHWmwVCh5cRBAp2eTtNm2yW5vdg_56t-hJGJiBeRgYhK4puaOE6UkTqdL0BI2o4BJTRd5Oh0yUxroQ8hxdpLQlhDAiihF6vQ-t3fmmzsrFHL9X0JkP_BKNyycs801jOsh8jH0DWfJ1Y8IRjb7z9dCkbBq-N-AjHHDwO8j2ptu0oa2_LtHZ2oQEV38-RuX8oZw94uXz4mk2XeK90AIXrlCs4mQtgOtKWyldNcgNktwoaQoFynGwUkmwhOWWSUcszVnFFDjBxuj2d3Z_aD97SN0q-mQhBNNA26dVTrQgOT-CN__AbdsfhjsDkzNKmeKE_QBNnV6g</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>223113740</pqid></control><display><type>article</type><title>Blocking TGF-[beta]-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology</title><source>SpringerLink Journals</source><source>Nature Journals Online</source><creator>Town, Terrence ; Laouar, Yasmina ; Pittenger, Christopher ; Mori, Takashi ; Szekely, Christine A ; Tan, Jun ; Duman, Ronald S ; Flavell, Richard A</creator><creatorcontrib>Town, Terrence ; Laouar, Yasmina ; Pittenger, Christopher ; Mori, Takashi ; Szekely, Christine A ; Tan, Jun ; Duman, Ronald S ; Flavell, Richard A</creatorcontrib><description>Alzheimer's disease is the most common dementia and is pathologically characterized by deposition of amyloid-[beta] peptide (A[beta]) into [beta]-amyloid plaques, neuronal injury and low-level, chronic activation of brain immunity. Transforming growth factor-[beta]s (TGF-[beta]s) are pleiotropic cytokines that have key roles in immune cell activation, inflammation and repair after injury. We genetically interrupted TGF-[beta] and downstream Smad2/3 signaling (TGF-[beta]-Smad2/3) in innate immune cells by inducing expression of CD11c promoter-driven dominant-negative TGF-[beta] receptor type II in C57BL/6 mice (CD11c-DNR)3, crossed these mice with mice overexpressing mutant human amyloid precursor protein, the Tg2576 Alzheimer's disease mouse model, and evaluated Alzheimer's disease-like pathology. Aged double-transgenic mice showed complete mitigation of Tg2576-associated hyperactivity and partial mitigation of defective spatial working memory. Brain parenchymal and cerebrovascular [beta]-amyloid deposits and A[beta] abundance were markedly (up to 90%) attenuated in Tg2576-CD11c-DNR mice. This was associated with increased infiltration of A[beta]-containing peripheral macrophages around cerebral vessels and [beta]-amyloid plaques. In vitro, cultures of peripheral macrophages, but not microglia, from CD11c-DNR mice showed blockade of classical TGF-[beta]-activated Smad2/3 but also showed hyperactivation of alternative bone morphogenic protein-activated Smad1/5/8 signaling and increased A[beta] phagocytosis. Similar effects were noted after pharmacological inhibition of activin-like kinase-5, a type I TGF-[beta] receptor. Taken together, our results suggest that blockade of TGF-[beta]-Smad2/3 signaling in peripheral macrophages represents a new therapeutic target for Alzheimer's disease. [PUBLICATION ABSTRACT]</description><identifier>ISSN: 1078-8956</identifier><identifier>EISSN: 1546-170X</identifier><identifier>DOI: 10.1038/nm1781</identifier><language>eng</language><publisher>New York: Nature Publishing Group</publisher><subject>Alzheimer's disease ; Dementia disorders ; Immunology ; Infiltration ; Medical research ; Pathology ; Rodents ; Signal transduction</subject><ispartof>Nature medicine, 2008-06, Vol.14 (6), p.681-687</ispartof><rights>Copyright Nature Publishing Group Jun 2008</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids></links><search><creatorcontrib>Town, Terrence</creatorcontrib><creatorcontrib>Laouar, Yasmina</creatorcontrib><creatorcontrib>Pittenger, Christopher</creatorcontrib><creatorcontrib>Mori, Takashi</creatorcontrib><creatorcontrib>Szekely, Christine A</creatorcontrib><creatorcontrib>Tan, Jun</creatorcontrib><creatorcontrib>Duman, Ronald S</creatorcontrib><creatorcontrib>Flavell, Richard A</creatorcontrib><title>Blocking TGF-[beta]-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology</title><title>Nature medicine</title><description>Alzheimer's disease is the most common dementia and is pathologically characterized by deposition of amyloid-[beta] peptide (A[beta]) into [beta]-amyloid plaques, neuronal injury and low-level, chronic activation of brain immunity. Transforming growth factor-[beta]s (TGF-[beta]s) are pleiotropic cytokines that have key roles in immune cell activation, inflammation and repair after injury. We genetically interrupted TGF-[beta] and downstream Smad2/3 signaling (TGF-[beta]-Smad2/3) in innate immune cells by inducing expression of CD11c promoter-driven dominant-negative TGF-[beta] receptor type II in C57BL/6 mice (CD11c-DNR)3, crossed these mice with mice overexpressing mutant human amyloid precursor protein, the Tg2576 Alzheimer's disease mouse model, and evaluated Alzheimer's disease-like pathology. Aged double-transgenic mice showed complete mitigation of Tg2576-associated hyperactivity and partial mitigation of defective spatial working memory. Brain parenchymal and cerebrovascular [beta]-amyloid deposits and A[beta] abundance were markedly (up to 90%) attenuated in Tg2576-CD11c-DNR mice. This was associated with increased infiltration of A[beta]-containing peripheral macrophages around cerebral vessels and [beta]-amyloid plaques. In vitro, cultures of peripheral macrophages, but not microglia, from CD11c-DNR mice showed blockade of classical TGF-[beta]-activated Smad2/3 but also showed hyperactivation of alternative bone morphogenic protein-activated Smad1/5/8 signaling and increased A[beta] phagocytosis. Similar effects were noted after pharmacological inhibition of activin-like kinase-5, a type I TGF-[beta] receptor. Taken together, our results suggest that blockade of TGF-[beta]-Smad2/3 signaling in peripheral macrophages represents a new therapeutic target for Alzheimer's disease. [PUBLICATION ABSTRACT]</description><subject>Alzheimer's disease</subject><subject>Dementia disorders</subject><subject>Immunology</subject><subject>Infiltration</subject><subject>Medical research</subject><subject>Pathology</subject><subject>Rodents</subject><subject>Signal transduction</subject><issn>1078-8956</issn><issn>1546-170X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdj01LAzEYhIMoWKv-hsWDt9hk87nHWmwVCh5cRBAp2eTtNm2yW5vdg_56t-hJGJiBeRgYhK4puaOE6UkTqdL0BI2o4BJTRd5Oh0yUxroQ8hxdpLQlhDAiihF6vQ-t3fmmzsrFHL9X0JkP_BKNyycs801jOsh8jH0DWfJ1Y8IRjb7z9dCkbBq-N-AjHHDwO8j2ptu0oa2_LtHZ2oQEV38-RuX8oZw94uXz4mk2XeK90AIXrlCs4mQtgOtKWyldNcgNktwoaQoFynGwUkmwhOWWSUcszVnFFDjBxuj2d3Z_aD97SN0q-mQhBNNA26dVTrQgOT-CN__AbdsfhjsDkzNKmeKE_QBNnV6g</recordid><startdate>20080601</startdate><enddate>20080601</enddate><creator>Town, Terrence</creator><creator>Laouar, Yasmina</creator><creator>Pittenger, Christopher</creator><creator>Mori, Takashi</creator><creator>Szekely, Christine A</creator><creator>Tan, Jun</creator><creator>Duman, Ronald S</creator><creator>Flavell, Richard A</creator><general>Nature Publishing Group</general><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U7</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M2P</scope><scope>M7N</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>RC3</scope></search><sort><creationdate>20080601</creationdate><title>Blocking TGF-[beta]-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology</title><author>Town, Terrence ; Laouar, Yasmina ; Pittenger, Christopher ; Mori, Takashi ; Szekely, Christine A ; Tan, Jun ; Duman, Ronald S ; Flavell, Richard A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p585-9d973b40f5e48b8c66db6dbddbd64a76a97e7d4ec676ec032c36d0c123b37ed53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Alzheimer's disease</topic><topic>Dementia disorders</topic><topic>Immunology</topic><topic>Infiltration</topic><topic>Medical research</topic><topic>Pathology</topic><topic>Rodents</topic><topic>Signal transduction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Town, Terrence</creatorcontrib><creatorcontrib>Laouar, Yasmina</creatorcontrib><creatorcontrib>Pittenger, Christopher</creatorcontrib><creatorcontrib>Mori, Takashi</creatorcontrib><creatorcontrib>Szekely, Christine A</creatorcontrib><creatorcontrib>Tan, Jun</creatorcontrib><creatorcontrib>Duman, Ronald S</creatorcontrib><creatorcontrib>Flavell, Richard A</creatorcontrib><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Science Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><jtitle>Nature medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Town, Terrence</au><au>Laouar, Yasmina</au><au>Pittenger, Christopher</au><au>Mori, Takashi</au><au>Szekely, Christine A</au><au>Tan, Jun</au><au>Duman, Ronald S</au><au>Flavell, Richard A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Blocking TGF-[beta]-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology</atitle><jtitle>Nature medicine</jtitle><date>2008-06-01</date><risdate>2008</risdate><volume>14</volume><issue>6</issue><spage>681</spage><epage>687</epage><pages>681-687</pages><issn>1078-8956</issn><eissn>1546-170X</eissn><abstract>Alzheimer's disease is the most common dementia and is pathologically characterized by deposition of amyloid-[beta] peptide (A[beta]) into [beta]-amyloid plaques, neuronal injury and low-level, chronic activation of brain immunity. Transforming growth factor-[beta]s (TGF-[beta]s) are pleiotropic cytokines that have key roles in immune cell activation, inflammation and repair after injury. We genetically interrupted TGF-[beta] and downstream Smad2/3 signaling (TGF-[beta]-Smad2/3) in innate immune cells by inducing expression of CD11c promoter-driven dominant-negative TGF-[beta] receptor type II in C57BL/6 mice (CD11c-DNR)3, crossed these mice with mice overexpressing mutant human amyloid precursor protein, the Tg2576 Alzheimer's disease mouse model, and evaluated Alzheimer's disease-like pathology. Aged double-transgenic mice showed complete mitigation of Tg2576-associated hyperactivity and partial mitigation of defective spatial working memory. Brain parenchymal and cerebrovascular [beta]-amyloid deposits and A[beta] abundance were markedly (up to 90%) attenuated in Tg2576-CD11c-DNR mice. This was associated with increased infiltration of A[beta]-containing peripheral macrophages around cerebral vessels and [beta]-amyloid plaques. In vitro, cultures of peripheral macrophages, but not microglia, from CD11c-DNR mice showed blockade of classical TGF-[beta]-activated Smad2/3 but also showed hyperactivation of alternative bone morphogenic protein-activated Smad1/5/8 signaling and increased A[beta] phagocytosis. Similar effects were noted after pharmacological inhibition of activin-like kinase-5, a type I TGF-[beta] receptor. Taken together, our results suggest that blockade of TGF-[beta]-Smad2/3 signaling in peripheral macrophages represents a new therapeutic target for Alzheimer's disease. [PUBLICATION ABSTRACT]</abstract><cop>New York</cop><pub>Nature Publishing Group</pub><doi>10.1038/nm1781</doi><tpages>7</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1078-8956 |
| ispartof | Nature medicine, 2008-06, Vol.14 (6), p.681-687 |
| issn | 1078-8956 1546-170X |
| language | eng |
| recordid | cdi_proquest_miscellaneous_20850245 |
| source | SpringerLink Journals; Nature Journals Online |
| subjects | Alzheimer's disease Dementia disorders Immunology Infiltration Medical research Pathology Rodents Signal transduction |
| title | Blocking TGF-[beta]-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-10T01%3A01%3A53IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Blocking%20TGF-%5Bbeta%5D-Smad2/3%20innate%20immune%20signaling%20mitigates%20Alzheimer-like%20pathology&rft.jtitle=Nature%20medicine&rft.au=Town,%20Terrence&rft.date=2008-06-01&rft.volume=14&rft.issue=6&rft.spage=681&rft.epage=687&rft.pages=681-687&rft.issn=1078-8956&rft.eissn=1546-170X&rft_id=info:doi/10.1038/nm1781&rft_dat=%3Cproquest%3E20850245%3C/proquest%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=223113740&rft_id=info:pmid/&rfr_iscdi=true |