Age-associated dysregulation of microglial activation is coupled with enhanced blood-brain barrier permeability and pathology in APP/PS1 mice
Abstract Aging adversely affects inflammatory processes in the brain, which has important implications in the context of disease progression. It has been proposed that microglia become dysfunctional with age and may lose their neuroprotective properties leading to chronic neurodegeneration. Here, we...
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| Veröffentlicht in: | Neurobiology of aging 2014-06, Vol.35 (6), p.1442-1452 |
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| container_title | Neurobiology of aging |
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| creator | Minogue, Aedín M Jones, Raasay S Kelly, Ronan J McDonald, Claire L Connor, Thomas J Lynch, Marina A |
| description | Abstract Aging adversely affects inflammatory processes in the brain, which has important implications in the context of disease progression. It has been proposed that microglia become dysfunctional with age and may lose their neuroprotective properties leading to chronic neurodegeneration. Here, we sought to characterize inflammatory changes in a mouse model of Alzheimer's disease and to delineate differences between normal aging and those associated with disease pathology. A proinflammatory profile, characterized by the upregulation of markers of classical activation, was evident in APPswe/PS1dE9 mice, associated with increased interferon-γ (IFNγ) concentration and dysregulation of mechanisms designed to limit the proinflammatory response. The data indicate that microglia are not less active with age but alter their phenotype; indeed, changes observed in the deactivation state appear to relate to aging rather than disease pathology. We hypothesize that disruption of the blood-brain barrier, in tandem with an enhanced chemokine profile, permits the infiltration of immune cells serving to reinforce classical activation of microglia through their enhanced responsiveness to IFNγ. |
| doi_str_mv | 10.1016/j.neurobiolaging.2013.12.026 |
| format | Article |
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It has been proposed that microglia become dysfunctional with age and may lose their neuroprotective properties leading to chronic neurodegeneration. Here, we sought to characterize inflammatory changes in a mouse model of Alzheimer's disease and to delineate differences between normal aging and those associated with disease pathology. A proinflammatory profile, characterized by the upregulation of markers of classical activation, was evident in APPswe/PS1dE9 mice, associated with increased interferon-γ (IFNγ) concentration and dysregulation of mechanisms designed to limit the proinflammatory response. The data indicate that microglia are not less active with age but alter their phenotype; indeed, changes observed in the deactivation state appear to relate to aging rather than disease pathology. We hypothesize that disruption of the blood-brain barrier, in tandem with an enhanced chemokine profile, permits the infiltration of immune cells serving to reinforce classical activation of microglia through their enhanced responsiveness to IFNγ.</description><identifier>ISSN: 0197-4580</identifier><identifier>EISSN: 1558-1497</identifier><identifier>DOI: 10.1016/j.neurobiolaging.2013.12.026</identifier><identifier>PMID: 24439957</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Aging - metabolism ; Aging - pathology ; Alzheimer Disease - genetics ; Alzheimer Disease - metabolism ; Alzheimer Disease - pathology ; Alzheimer's disease ; Amyloid beta-Protein Precursor - genetics ; Animals ; Blood-Brain Barrier - metabolism ; Blood-Brain Barrier - pathology ; Blood-brain barrier permeability ; Disease Models, Animal ; Female ; Infiltrating immune cells ; Inflammation Mediators - metabolism ; Interferon-gamma - metabolism ; Interferon-γ ; Internal Medicine ; Male ; Mice ; Mice, Inbred C57BL ; Microglia - pathology ; Microglial activation states ; Mutation ; Neurology ; Permeability ; Presenilin-1 - genetics ; Up-Regulation</subject><ispartof>Neurobiology of aging, 2014-06, Vol.35 (6), p.1442-1452</ispartof><rights>Elsevier Inc.</rights><rights>2014 Elsevier Inc.</rights><rights>Copyright © 2014 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c544t-48f89c6a94e37149ed57dcba993e0ca240de007964bff22e21ba34d694fc22df3</citedby><cites>FETCH-LOGICAL-c544t-48f89c6a94e37149ed57dcba993e0ca240de007964bff22e21ba34d694fc22df3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0197458013006684$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,65309</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24439957$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Minogue, Aedín M</creatorcontrib><creatorcontrib>Jones, Raasay S</creatorcontrib><creatorcontrib>Kelly, Ronan J</creatorcontrib><creatorcontrib>McDonald, Claire L</creatorcontrib><creatorcontrib>Connor, Thomas J</creatorcontrib><creatorcontrib>Lynch, Marina A</creatorcontrib><title>Age-associated dysregulation of microglial activation is coupled with enhanced blood-brain barrier permeability and pathology in APP/PS1 mice</title><title>Neurobiology of aging</title><addtitle>Neurobiol Aging</addtitle><description>Abstract Aging adversely affects inflammatory processes in the brain, which has important implications in the context of disease progression. It has been proposed that microglia become dysfunctional with age and may lose their neuroprotective properties leading to chronic neurodegeneration. Here, we sought to characterize inflammatory changes in a mouse model of Alzheimer's disease and to delineate differences between normal aging and those associated with disease pathology. A proinflammatory profile, characterized by the upregulation of markers of classical activation, was evident in APPswe/PS1dE9 mice, associated with increased interferon-γ (IFNγ) concentration and dysregulation of mechanisms designed to limit the proinflammatory response. The data indicate that microglia are not less active with age but alter their phenotype; indeed, changes observed in the deactivation state appear to relate to aging rather than disease pathology. We hypothesize that disruption of the blood-brain barrier, in tandem with an enhanced chemokine profile, permits the infiltration of immune cells serving to reinforce classical activation of microglia through their enhanced responsiveness to IFNγ.</description><subject>Aging - metabolism</subject><subject>Aging - pathology</subject><subject>Alzheimer Disease - genetics</subject><subject>Alzheimer Disease - metabolism</subject><subject>Alzheimer Disease - pathology</subject><subject>Alzheimer's disease</subject><subject>Amyloid beta-Protein Precursor - genetics</subject><subject>Animals</subject><subject>Blood-Brain Barrier - metabolism</subject><subject>Blood-Brain Barrier - pathology</subject><subject>Blood-brain barrier permeability</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>Infiltrating immune cells</subject><subject>Inflammation Mediators - metabolism</subject><subject>Interferon-gamma - metabolism</subject><subject>Interferon-γ</subject><subject>Internal Medicine</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Microglia - pathology</subject><subject>Microglial activation states</subject><subject>Mutation</subject><subject>Neurology</subject><subject>Permeability</subject><subject>Presenilin-1 - genetics</subject><subject>Up-Regulation</subject><issn>0197-4580</issn><issn>1558-1497</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkt-K1TAQxoMo7nH1FSQXXnjTbpKmfwIiHBZXhQUPrF6HNJn25Jg2NWlX-hC-sylnFfRqr8KQ75thft8g9IaSnBJaXZ3yEZbgW-ud6u3Y54zQIqcsJ6x6gna0LJuMclE_RTtCRZ3xsiEX6EWMJ0JIzevqObpgnBdClPUO_dr3kKkYvbZqBoPNGgP0i1Oz9SP2HR6sDr53Vjms9Gzvzx82Yu2XySXHTzsfMYxHNepUtc57k7VB2RG3KgQLAU8QBlCtdXZesRoNntR89M73K06q_eFwdbij2yB4iZ51ykV49fBeom83H75ef8puv3z8fL2_zXTJ-ZzxpmuErpTgUNRpVzBlbXSrhCiAaMU4MZB2FRVvu44xYLRVBTeV4J1mzHTFJXp77jsF_2OBOMvBRg3OqRH8EiUtGSmasiTsEVLSCF4WbJO-O0sTsZgwdnIKdlBhlZTILTt5kv9mJ7fsJGUyZZfsrx8mLe0A5q_5T1hJcHMWQEJzn8jKqC1s2G0APUvj7WMnvf-vkXZ2tFq577BCPPkljAm_pDImg7zb7mg7I1oQUlUNL34DPIXK1w</recordid><startdate>20140601</startdate><enddate>20140601</enddate><creator>Minogue, Aedín M</creator><creator>Jones, Raasay S</creator><creator>Kelly, Ronan J</creator><creator>McDonald, Claire L</creator><creator>Connor, Thomas J</creator><creator>Lynch, Marina A</creator><general>Elsevier 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>7X8</scope><scope>7TK</scope></search><sort><creationdate>20140601</creationdate><title>Age-associated dysregulation of microglial activation is coupled with enhanced blood-brain barrier permeability and pathology in APP/PS1 mice</title><author>Minogue, Aedín M ; Jones, Raasay S ; Kelly, Ronan J ; McDonald, Claire L ; Connor, Thomas J ; Lynch, Marina A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c544t-48f89c6a94e37149ed57dcba993e0ca240de007964bff22e21ba34d694fc22df3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Aging - metabolism</topic><topic>Aging - pathology</topic><topic>Alzheimer Disease - genetics</topic><topic>Alzheimer Disease - metabolism</topic><topic>Alzheimer Disease - pathology</topic><topic>Alzheimer's disease</topic><topic>Amyloid beta-Protein Precursor - genetics</topic><topic>Animals</topic><topic>Blood-Brain Barrier - metabolism</topic><topic>Blood-Brain Barrier - pathology</topic><topic>Blood-brain barrier permeability</topic><topic>Disease Models, Animal</topic><topic>Female</topic><topic>Infiltrating immune cells</topic><topic>Inflammation Mediators - metabolism</topic><topic>Interferon-gamma - metabolism</topic><topic>Interferon-γ</topic><topic>Internal Medicine</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Microglia - pathology</topic><topic>Microglial activation states</topic><topic>Mutation</topic><topic>Neurology</topic><topic>Permeability</topic><topic>Presenilin-1 - genetics</topic><topic>Up-Regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Minogue, Aedín M</creatorcontrib><creatorcontrib>Jones, Raasay S</creatorcontrib><creatorcontrib>Kelly, Ronan J</creatorcontrib><creatorcontrib>McDonald, Claire L</creatorcontrib><creatorcontrib>Connor, Thomas J</creatorcontrib><creatorcontrib>Lynch, Marina A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Neurosciences Abstracts</collection><jtitle>Neurobiology of aging</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Minogue, Aedín M</au><au>Jones, Raasay S</au><au>Kelly, Ronan J</au><au>McDonald, Claire L</au><au>Connor, Thomas J</au><au>Lynch, Marina A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Age-associated dysregulation of microglial activation is coupled with enhanced blood-brain barrier permeability and pathology in APP/PS1 mice</atitle><jtitle>Neurobiology of aging</jtitle><addtitle>Neurobiol Aging</addtitle><date>2014-06-01</date><risdate>2014</risdate><volume>35</volume><issue>6</issue><spage>1442</spage><epage>1452</epage><pages>1442-1452</pages><issn>0197-4580</issn><eissn>1558-1497</eissn><abstract>Abstract Aging adversely affects inflammatory processes in the brain, which has important implications in the context of disease progression. It has been proposed that microglia become dysfunctional with age and may lose their neuroprotective properties leading to chronic neurodegeneration. Here, we sought to characterize inflammatory changes in a mouse model of Alzheimer's disease and to delineate differences between normal aging and those associated with disease pathology. A proinflammatory profile, characterized by the upregulation of markers of classical activation, was evident in APPswe/PS1dE9 mice, associated with increased interferon-γ (IFNγ) concentration and dysregulation of mechanisms designed to limit the proinflammatory response. The data indicate that microglia are not less active with age but alter their phenotype; indeed, changes observed in the deactivation state appear to relate to aging rather than disease pathology. 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| subjects | Aging - metabolism Aging - pathology Alzheimer Disease - genetics Alzheimer Disease - metabolism Alzheimer Disease - pathology Alzheimer's disease Amyloid beta-Protein Precursor - genetics Animals Blood-Brain Barrier - metabolism Blood-Brain Barrier - pathology Blood-brain barrier permeability Disease Models, Animal Female Infiltrating immune cells Inflammation Mediators - metabolism Interferon-gamma - metabolism Interferon-γ Internal Medicine Male Mice Mice, Inbred C57BL Microglia - pathology Microglial activation states Mutation Neurology Permeability Presenilin-1 - genetics Up-Regulation |
| title | Age-associated dysregulation of microglial activation is coupled with enhanced blood-brain barrier permeability and pathology in APP/PS1 mice |
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