Annexin A1 restores Aβ 1-42 -induced blood-brain barrier disruption through the inhibition of RhoA-ROCK signaling pathway

The blood-brain barrier (BBB) is composed of brain capillary endothelial cells and has an important role in maintaining homeostasis of the brain separating the blood from the parenchyma of the central nervous system (CNS). It is widely known that disruption of the BBB occurs in various neurodegenera...

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Veröffentlicht in:Aging cell 2017-02, Vol.16 (1), p.149-161
Hauptverfasser: Park, Jong-Chan, Baik, Sung Hoon, Han, Sun-Ho, Cho, Hyun Jin, Choi, Hyunjung, Kim, Haeng Jun, Choi, Heesun, Lee, Wonik, Kim, Dong Kyu, Mook-Jung, Inhee
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container_end_page 161
container_issue 1
container_start_page 149
container_title Aging cell
container_volume 16
creator Park, Jong-Chan
Baik, Sung Hoon
Han, Sun-Ho
Cho, Hyun Jin
Choi, Hyunjung
Kim, Haeng Jun
Choi, Heesun
Lee, Wonik
Kim, Dong Kyu
Mook-Jung, Inhee
description The blood-brain barrier (BBB) is composed of brain capillary endothelial cells and has an important role in maintaining homeostasis of the brain separating the blood from the parenchyma of the central nervous system (CNS). It is widely known that disruption of the BBB occurs in various neurodegenerative diseases, including Alzheimer's disease (AD). Annexin A1 (ANXA1), an anti-inflammatory messenger, is expressed in brain endothelial cells and regulates the BBB integrity. However, its role and mechanism for protecting BBB in AD have not been identified. We found that β-Amyloid 1-42 (Aβ42)-induced BBB disruption was rescued by human recombinant ANXA1 (hrANXA1) in the murine brain endothelial cell line bEnd.3. Also, ANXA1 was decreased in the bEnd.3 cells, the capillaries of 5XFAD mice, and the human serum of patients with AD. To find out the mechanism by which ANXA1 recovers the BBB integrity in AD, the RhoA-ROCK signaling pathway was examined in both Aβ42-treated bEnd.3 cells and the capillaries of 5XFAD mice as RhoA was activated in both cases. RhoA inhibitors alleviated Aβ42-induced BBB disruption and constitutively overexpressed RhoA-GTP (active form of RhoA) attenuated the protective effect of ANXA1. When pericytes were cocultured with bEnd.3 cells, Aβ42-induced RhoA activation of bEnd.3 cells was inhibited by the secretion of ANXA1 from pericytes. Taken together, our results suggest that ANXA1 restores Aβ42-induced BBB disruption through inhibition of RhoA-ROCK signaling pathway and we propose ANXA1 as a therapeutic reagent, protecting against the breakdown of the BBB in AD.
doi_str_mv 10.1111/acel.12530
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It is widely known that disruption of the BBB occurs in various neurodegenerative diseases, including Alzheimer's disease (AD). Annexin A1 (ANXA1), an anti-inflammatory messenger, is expressed in brain endothelial cells and regulates the BBB integrity. However, its role and mechanism for protecting BBB in AD have not been identified. We found that β-Amyloid 1-42 (Aβ42)-induced BBB disruption was rescued by human recombinant ANXA1 (hrANXA1) in the murine brain endothelial cell line bEnd.3. Also, ANXA1 was decreased in the bEnd.3 cells, the capillaries of 5XFAD mice, and the human serum of patients with AD. To find out the mechanism by which ANXA1 recovers the BBB integrity in AD, the RhoA-ROCK signaling pathway was examined in both Aβ42-treated bEnd.3 cells and the capillaries of 5XFAD mice as RhoA was activated in both cases. RhoA inhibitors alleviated Aβ42-induced BBB disruption and constitutively overexpressed RhoA-GTP (active form of RhoA) attenuated the protective effect of ANXA1. When pericytes were cocultured with bEnd.3 cells, Aβ42-induced RhoA activation of bEnd.3 cells was inhibited by the secretion of ANXA1 from pericytes. Taken together, our results suggest that ANXA1 restores Aβ42-induced BBB disruption through inhibition of RhoA-ROCK signaling pathway and we propose ANXA1 as a therapeutic reagent, protecting against the breakdown of the BBB in AD.</description><identifier>ISSN: 1474-9718</identifier><identifier>EISSN: 1474-9726</identifier><identifier>DOI: 10.1111/acel.12530</identifier><identifier>PMID: 27633771</identifier><language>eng</language><publisher>England</publisher><subject>Aged ; Alzheimer Disease - blood ; Alzheimer Disease - pathology ; Amyloid beta-Peptides - toxicity ; Animals ; Annexin A1 - blood ; Annexin A1 - metabolism ; Blood-Brain Barrier - drug effects ; Blood-Brain Barrier - metabolism ; Blood-Brain Barrier - pathology ; Capillaries - drug effects ; Capillaries - metabolism ; Female ; Humans ; Male ; Mice, Transgenic ; Peptide Fragments - toxicity ; Pericytes - drug effects ; Pericytes - metabolism ; Receptors, Formyl Peptide - blood ; Receptors, Lipoxin - blood ; Recombinant Proteins - pharmacology ; rho-Associated Kinases - antagonists &amp; inhibitors ; rho-Associated Kinases - metabolism ; rhoA GTP-Binding Protein - metabolism ; Signal Transduction - drug effects ; Tight Junctions - drug effects ; Tight Junctions - metabolism</subject><ispartof>Aging cell, 2017-02, Vol.16 (1), p.149-161</ispartof><rights>2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley &amp; Sons Ltd.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c991-761d890441be1a867f088db819872374b888f52f21a9e16abc691e3a2e8febd23</citedby><cites>FETCH-LOGICAL-c991-761d890441be1a867f088db819872374b888f52f21a9e16abc691e3a2e8febd23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,864,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27633771$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Park, Jong-Chan</creatorcontrib><creatorcontrib>Baik, Sung Hoon</creatorcontrib><creatorcontrib>Han, Sun-Ho</creatorcontrib><creatorcontrib>Cho, Hyun Jin</creatorcontrib><creatorcontrib>Choi, Hyunjung</creatorcontrib><creatorcontrib>Kim, Haeng Jun</creatorcontrib><creatorcontrib>Choi, Heesun</creatorcontrib><creatorcontrib>Lee, Wonik</creatorcontrib><creatorcontrib>Kim, Dong Kyu</creatorcontrib><creatorcontrib>Mook-Jung, Inhee</creatorcontrib><title>Annexin A1 restores Aβ 1-42 -induced blood-brain barrier disruption through the inhibition of RhoA-ROCK signaling pathway</title><title>Aging cell</title><addtitle>Aging Cell</addtitle><description>The blood-brain barrier (BBB) is composed of brain capillary endothelial cells and has an important role in maintaining homeostasis of the brain separating the blood from the parenchyma of the central nervous system (CNS). 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When pericytes were cocultured with bEnd.3 cells, Aβ42-induced RhoA activation of bEnd.3 cells was inhibited by the secretion of ANXA1 from pericytes. Taken together, our results suggest that ANXA1 restores Aβ42-induced BBB disruption through inhibition of RhoA-ROCK signaling pathway and we propose ANXA1 as a therapeutic reagent, protecting against the breakdown of the BBB in AD.</description><subject>Aged</subject><subject>Alzheimer Disease - blood</subject><subject>Alzheimer Disease - pathology</subject><subject>Amyloid beta-Peptides - toxicity</subject><subject>Animals</subject><subject>Annexin A1 - blood</subject><subject>Annexin A1 - metabolism</subject><subject>Blood-Brain Barrier - drug effects</subject><subject>Blood-Brain Barrier - metabolism</subject><subject>Blood-Brain Barrier - pathology</subject><subject>Capillaries - drug effects</subject><subject>Capillaries - metabolism</subject><subject>Female</subject><subject>Humans</subject><subject>Male</subject><subject>Mice, Transgenic</subject><subject>Peptide Fragments - toxicity</subject><subject>Pericytes - drug effects</subject><subject>Pericytes - metabolism</subject><subject>Receptors, Formyl Peptide - blood</subject><subject>Receptors, Lipoxin - blood</subject><subject>Recombinant Proteins - pharmacology</subject><subject>rho-Associated Kinases - antagonists &amp; inhibitors</subject><subject>rho-Associated Kinases - metabolism</subject><subject>rhoA GTP-Binding Protein - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>Tight Junctions - drug effects</subject><subject>Tight Junctions - metabolism</subject><issn>1474-9718</issn><issn>1474-9726</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kN9KwzAUh4Mobk5vfADJtZCZk3ZNclmG_3AwGLsvSZOuka4paYvOx_JBfCa7TXcuzu_H4eNcfAjdAp3CMA8qt9UU2CyiZ2gMMY-J5Cw5P3UQI3TVtu-UApc0ukQjxpMo4hzG6Cuta_vpapwCDrbt_LBw-vONgcQME1ebPrcG68p7Q3RQA6lVCM4GbFwb-qZzvsZdGXy_KYe02NWl0-5w9gVelT4lq-X8DbduU6vK1RvcqK78ULtrdFGoqrU3fzlB66fH9fyFLJbPr_N0QXIpgfAEjJA0jkFbUCLhBRXCaAFScBbxWAshihkrGChpIVE6TyTYSDErCqsNiybo_vg2D75tgy2yJritCrsMaLb3l-39ZQd_A3x3hJteb605of_Col-HK2xK</recordid><startdate>201702</startdate><enddate>201702</enddate><creator>Park, Jong-Chan</creator><creator>Baik, Sung Hoon</creator><creator>Han, Sun-Ho</creator><creator>Cho, Hyun Jin</creator><creator>Choi, Hyunjung</creator><creator>Kim, Haeng Jun</creator><creator>Choi, Heesun</creator><creator>Lee, Wonik</creator><creator>Kim, Dong Kyu</creator><creator>Mook-Jung, Inhee</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>201702</creationdate><title>Annexin A1 restores Aβ 1-42 -induced blood-brain barrier disruption through the inhibition of RhoA-ROCK signaling pathway</title><author>Park, Jong-Chan ; 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inhibitors</topic><topic>rho-Associated Kinases - metabolism</topic><topic>rhoA GTP-Binding Protein - metabolism</topic><topic>Signal Transduction - drug effects</topic><topic>Tight Junctions - drug effects</topic><topic>Tight Junctions - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Park, Jong-Chan</creatorcontrib><creatorcontrib>Baik, Sung Hoon</creatorcontrib><creatorcontrib>Han, Sun-Ho</creatorcontrib><creatorcontrib>Cho, Hyun Jin</creatorcontrib><creatorcontrib>Choi, Hyunjung</creatorcontrib><creatorcontrib>Kim, Haeng Jun</creatorcontrib><creatorcontrib>Choi, Heesun</creatorcontrib><creatorcontrib>Lee, Wonik</creatorcontrib><creatorcontrib>Kim, Dong Kyu</creatorcontrib><creatorcontrib>Mook-Jung, Inhee</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Aging cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Park, Jong-Chan</au><au>Baik, Sung Hoon</au><au>Han, Sun-Ho</au><au>Cho, Hyun Jin</au><au>Choi, Hyunjung</au><au>Kim, Haeng Jun</au><au>Choi, Heesun</au><au>Lee, Wonik</au><au>Kim, Dong Kyu</au><au>Mook-Jung, Inhee</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Annexin A1 restores Aβ 1-42 -induced blood-brain barrier disruption through the inhibition of RhoA-ROCK signaling pathway</atitle><jtitle>Aging cell</jtitle><addtitle>Aging Cell</addtitle><date>2017-02</date><risdate>2017</risdate><volume>16</volume><issue>1</issue><spage>149</spage><epage>161</epage><pages>149-161</pages><issn>1474-9718</issn><eissn>1474-9726</eissn><abstract>The blood-brain barrier (BBB) is composed of brain capillary endothelial cells and has an important role in maintaining homeostasis of the brain separating the blood from the parenchyma of the central nervous system (CNS). It is widely known that disruption of the BBB occurs in various neurodegenerative diseases, including Alzheimer's disease (AD). Annexin A1 (ANXA1), an anti-inflammatory messenger, is expressed in brain endothelial cells and regulates the BBB integrity. However, its role and mechanism for protecting BBB in AD have not been identified. We found that β-Amyloid 1-42 (Aβ42)-induced BBB disruption was rescued by human recombinant ANXA1 (hrANXA1) in the murine brain endothelial cell line bEnd.3. Also, ANXA1 was decreased in the bEnd.3 cells, the capillaries of 5XFAD mice, and the human serum of patients with AD. To find out the mechanism by which ANXA1 recovers the BBB integrity in AD, the RhoA-ROCK signaling pathway was examined in both Aβ42-treated bEnd.3 cells and the capillaries of 5XFAD mice as RhoA was activated in both cases. RhoA inhibitors alleviated Aβ42-induced BBB disruption and constitutively overexpressed RhoA-GTP (active form of RhoA) attenuated the protective effect of ANXA1. When pericytes were cocultured with bEnd.3 cells, Aβ42-induced RhoA activation of bEnd.3 cells was inhibited by the secretion of ANXA1 from pericytes. Taken together, our results suggest that ANXA1 restores Aβ42-induced BBB disruption through inhibition of RhoA-ROCK signaling pathway and we propose ANXA1 as a therapeutic reagent, protecting against the breakdown of the BBB in AD.</abstract><cop>England</cop><pmid>27633771</pmid><doi>10.1111/acel.12530</doi><tpages>13</tpages></addata></record>
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source PubMed (Medline); MEDLINE; Wiley Online Library; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; Wiley Online Library All Journals; Alma/SFX Local Collection
subjects Aged
Alzheimer Disease - blood
Alzheimer Disease - pathology
Amyloid beta-Peptides - toxicity
Animals
Annexin A1 - blood
Annexin A1 - metabolism
Blood-Brain Barrier - drug effects
Blood-Brain Barrier - metabolism
Blood-Brain Barrier - pathology
Capillaries - drug effects
Capillaries - metabolism
Female
Humans
Male
Mice, Transgenic
Peptide Fragments - toxicity
Pericytes - drug effects
Pericytes - metabolism
Receptors, Formyl Peptide - blood
Receptors, Lipoxin - blood
Recombinant Proteins - pharmacology
rho-Associated Kinases - antagonists & inhibitors
rho-Associated Kinases - metabolism
rhoA GTP-Binding Protein - metabolism
Signal Transduction - drug effects
Tight Junctions - drug effects
Tight Junctions - metabolism
title Annexin A1 restores Aβ 1-42 -induced blood-brain barrier disruption through the inhibition of RhoA-ROCK signaling pathway
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