Deletion of the type-1 interferon receptor in APPSWE/PS1ΔE9 mice preserves cognitive function and alters glial phenotype
A neuro-inflammatory response is evident in Alzheimer's disease (AD), yet the precise mechanisms by which neuro-inflammation influences the progression of Alzheimer's disease (AD) remain poorly understood. Type-1 interferons (IFNs) are master regulators of innate immunity and have been imp...
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| Veröffentlicht in: | Acta neuropathologica communications 2016-07, Vol.4 (1), p.72-72, Article 72 |
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| creator | Minter, Myles R Moore, Zachery Zhang, Moses Brody, Kate M Jones, Nigel C Shultz, Sandy R Taylor, Juliet M Crack, Peter J |
| description | A neuro-inflammatory response is evident in Alzheimer's disease (AD), yet the precise mechanisms by which neuro-inflammation influences the progression of Alzheimer's disease (AD) remain poorly understood. Type-1 interferons (IFNs) are master regulators of innate immunity and have been implicated in multiple CNS disorders, however their role in AD progression has not yet been fully investigated. Hence, we generated APPSWE/PS1ΔE9 mice lacking the type-1 IFN alpha receptor-1 (IFNAR1, APPSWE/PS1ΔE9 x IFNAR1(-/-)) aged to 9 months to investigate the role of type-1 IFN signaling in a well-validated model of AD. APPSWE/PS1ΔE9 x IFNAR1(-/-) mice displayed a modest reduction in Aβ monomer levels, despite maintenance of plaque deposition. This finding correlated with partial rescue of spatial learning and memory impairments in the Morris water maze in comparison to APPSWE/PS1ΔE9 mice. Q-PCR identified a reduced type-1 IFN response and modulated pro-inflammatory cytokine secretion in APPSWE/PS1ΔE9 x IFNAR1(-/-) mice compared to APPSWE/PS1ΔE9 mice. Interestingly, immunohistochemistry displayed enhanced astrocyte reactivity but attenuated microgliosis surrounding amyloid plaque deposits in APPSWE/PS1ΔE9 x IFNAR1(-/-) mice in comparison to APPSWE/PS1ΔE9 mice. These APPSWE/PS1ΔE9 x IFNAR1(-/-) microglial populations demonstrated an anti-inflammatory phenotype that was confirmed in vitro by soluble Aβ1-42 treatment of IFNAR1(-/-) primary glial cultures. Our findings suggest that modulating neuro-inflammatory responses by suppressing type-1 IFN signaling may provide therapeutic benefit in AD. |
| doi_str_mv | 10.1186/s40478-016-0341-4 |
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Type-1 interferons (IFNs) are master regulators of innate immunity and have been implicated in multiple CNS disorders, however their role in AD progression has not yet been fully investigated. Hence, we generated APPSWE/PS1ΔE9 mice lacking the type-1 IFN alpha receptor-1 (IFNAR1, APPSWE/PS1ΔE9 x IFNAR1(-/-)) aged to 9 months to investigate the role of type-1 IFN signaling in a well-validated model of AD. APPSWE/PS1ΔE9 x IFNAR1(-/-) mice displayed a modest reduction in Aβ monomer levels, despite maintenance of plaque deposition. This finding correlated with partial rescue of spatial learning and memory impairments in the Morris water maze in comparison to APPSWE/PS1ΔE9 mice. Q-PCR identified a reduced type-1 IFN response and modulated pro-inflammatory cytokine secretion in APPSWE/PS1ΔE9 x IFNAR1(-/-) mice compared to APPSWE/PS1ΔE9 mice. Interestingly, immunohistochemistry displayed enhanced astrocyte reactivity but attenuated microgliosis surrounding amyloid plaque deposits in APPSWE/PS1ΔE9 x IFNAR1(-/-) mice in comparison to APPSWE/PS1ΔE9 mice. These APPSWE/PS1ΔE9 x IFNAR1(-/-) microglial populations demonstrated an anti-inflammatory phenotype that was confirmed in vitro by soluble Aβ1-42 treatment of IFNAR1(-/-) primary glial cultures. Our findings suggest that modulating neuro-inflammatory responses by suppressing type-1 IFN signaling may provide therapeutic benefit in AD.</description><identifier>ISSN: 2051-5960</identifier><identifier>EISSN: 2051-5960</identifier><identifier>DOI: 10.1186/s40478-016-0341-4</identifier><identifier>PMID: 27400725</identifier><language>eng</language><publisher>England: BioMed Central</publisher><subject>Alzheimer Disease - immunology ; Alzheimer Disease - pathology ; Alzheimer Disease - psychology ; Amyloid beta-Peptides - metabolism ; Animals ; Cells, Cultured ; Cerebral Cortex - immunology ; Cerebral Cortex - pathology ; Cognition - physiology ; Disease Models, Animal ; Female ; Gliosis - immunology ; Gliosis - pathology ; Gliosis - psychology ; Hippocampus - immunology ; Hippocampus - pathology ; Humans ; Male ; Maze Learning - physiology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neuroglia - immunology ; Neuroglia - pathology ; Neurons - immunology ; Neurons - pathology ; Peptide Fragments - metabolism ; Plaque, Amyloid - immunology ; Plaque, Amyloid - pathology ; Plaque, Amyloid - psychology ; Receptor, Interferon alpha-beta - deficiency ; Receptor, Interferon alpha-beta - genetics ; Spatial Memory - physiology</subject><ispartof>Acta neuropathologica communications, 2016-07, Vol.4 (1), p.72-72, Article 72</ispartof><rights>The Author(s). 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c399t-1533729845ea771070d334c61dcc97b4870ccc68ebd3a5ace8939a02e5eca9c03</citedby><cites>FETCH-LOGICAL-c399t-1533729845ea771070d334c61dcc97b4870ccc68ebd3a5ace8939a02e5eca9c03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940712/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940712/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27400725$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Minter, Myles R</creatorcontrib><creatorcontrib>Moore, Zachery</creatorcontrib><creatorcontrib>Zhang, Moses</creatorcontrib><creatorcontrib>Brody, Kate M</creatorcontrib><creatorcontrib>Jones, Nigel C</creatorcontrib><creatorcontrib>Shultz, Sandy R</creatorcontrib><creatorcontrib>Taylor, Juliet M</creatorcontrib><creatorcontrib>Crack, Peter J</creatorcontrib><title>Deletion of the type-1 interferon receptor in APPSWE/PS1ΔE9 mice preserves cognitive function and alters glial phenotype</title><title>Acta neuropathologica communications</title><addtitle>Acta Neuropathol Commun</addtitle><description>A neuro-inflammatory response is evident in Alzheimer's disease (AD), yet the precise mechanisms by which neuro-inflammation influences the progression of Alzheimer's disease (AD) remain poorly understood. Type-1 interferons (IFNs) are master regulators of innate immunity and have been implicated in multiple CNS disorders, however their role in AD progression has not yet been fully investigated. Hence, we generated APPSWE/PS1ΔE9 mice lacking the type-1 IFN alpha receptor-1 (IFNAR1, APPSWE/PS1ΔE9 x IFNAR1(-/-)) aged to 9 months to investigate the role of type-1 IFN signaling in a well-validated model of AD. APPSWE/PS1ΔE9 x IFNAR1(-/-) mice displayed a modest reduction in Aβ monomer levels, despite maintenance of plaque deposition. This finding correlated with partial rescue of spatial learning and memory impairments in the Morris water maze in comparison to APPSWE/PS1ΔE9 mice. Q-PCR identified a reduced type-1 IFN response and modulated pro-inflammatory cytokine secretion in APPSWE/PS1ΔE9 x IFNAR1(-/-) mice compared to APPSWE/PS1ΔE9 mice. Interestingly, immunohistochemistry displayed enhanced astrocyte reactivity but attenuated microgliosis surrounding amyloid plaque deposits in APPSWE/PS1ΔE9 x IFNAR1(-/-) mice in comparison to APPSWE/PS1ΔE9 mice. These APPSWE/PS1ΔE9 x IFNAR1(-/-) microglial populations demonstrated an anti-inflammatory phenotype that was confirmed in vitro by soluble Aβ1-42 treatment of IFNAR1(-/-) primary glial cultures. Our findings suggest that modulating neuro-inflammatory responses by suppressing type-1 IFN signaling may provide therapeutic benefit in AD.</description><subject>Alzheimer Disease - immunology</subject><subject>Alzheimer Disease - pathology</subject><subject>Alzheimer Disease - psychology</subject><subject>Amyloid beta-Peptides - metabolism</subject><subject>Animals</subject><subject>Cells, Cultured</subject><subject>Cerebral Cortex - immunology</subject><subject>Cerebral Cortex - pathology</subject><subject>Cognition - physiology</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>Gliosis - immunology</subject><subject>Gliosis - pathology</subject><subject>Gliosis - psychology</subject><subject>Hippocampus - immunology</subject><subject>Hippocampus - pathology</subject><subject>Humans</subject><subject>Male</subject><subject>Maze Learning - physiology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Transgenic</subject><subject>Neuroglia - immunology</subject><subject>Neuroglia - pathology</subject><subject>Neurons - immunology</subject><subject>Neurons - pathology</subject><subject>Peptide Fragments - metabolism</subject><subject>Plaque, Amyloid - immunology</subject><subject>Plaque, Amyloid - pathology</subject><subject>Plaque, Amyloid - psychology</subject><subject>Receptor, Interferon alpha-beta - deficiency</subject><subject>Receptor, Interferon alpha-beta - genetics</subject><subject>Spatial Memory - physiology</subject><issn>2051-5960</issn><issn>2051-5960</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkc1qGzEQgEVJaUKaB-il6JjLNpqVdiVdCiFxk0IghrT0KGTtrK2yljaSbPB75Ln6TF3XaUh0GTE_3wx8hHwC9gVAtRdZMCFVxaCtGBdQiXfkpGYNVI1u2dGr_zE5y_k3m54G4Ep9IMe1FIzJujkhu2scsPgYaOxpWSEtuxEroD4UTD2mqZDQ4VhimnL0cj5_-DW7mD_An6eZpmvvkI4JM6YtZuriMvjit0j7TXD_qDZ01A4TK9Pl4O1AxxWGuF_ykbzv7ZDx7Dmekp_fZj-ubqu7-5vvV5d3leNalwoazmWtlWjQSglMso5z4VronNNyIZRkzrlW4aLjtrEOlebashobdFY7xk_J1wN33CzW2DkMJdnBjMmvbdqZaL15Wwl-ZZZxa4QWTEI9Ac6fASk-bjAXs_bZ4TDYgHGTDSjGpa5b3U6tcGh1KeacsH9ZA8zsrZmDNTNZM3trRkwzn1_f9zLx3xH_C2LTlRY</recordid><startdate>20160711</startdate><enddate>20160711</enddate><creator>Minter, Myles R</creator><creator>Moore, Zachery</creator><creator>Zhang, Moses</creator><creator>Brody, Kate M</creator><creator>Jones, Nigel C</creator><creator>Shultz, Sandy R</creator><creator>Taylor, Juliet M</creator><creator>Crack, Peter J</creator><general>BioMed Central</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>5PM</scope></search><sort><creationdate>20160711</creationdate><title>Deletion of the type-1 interferon receptor in APPSWE/PS1ΔE9 mice preserves cognitive function and alters glial phenotype</title><author>Minter, Myles R ; Moore, Zachery ; Zhang, Moses ; Brody, Kate M ; Jones, Nigel C ; Shultz, Sandy R ; Taylor, Juliet M ; Crack, Peter J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c399t-1533729845ea771070d334c61dcc97b4870ccc68ebd3a5ace8939a02e5eca9c03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Alzheimer Disease - immunology</topic><topic>Alzheimer Disease - pathology</topic><topic>Alzheimer Disease - psychology</topic><topic>Amyloid beta-Peptides - metabolism</topic><topic>Animals</topic><topic>Cells, Cultured</topic><topic>Cerebral Cortex - immunology</topic><topic>Cerebral Cortex - pathology</topic><topic>Cognition - physiology</topic><topic>Disease Models, Animal</topic><topic>Female</topic><topic>Gliosis - immunology</topic><topic>Gliosis - pathology</topic><topic>Gliosis - psychology</topic><topic>Hippocampus - immunology</topic><topic>Hippocampus - pathology</topic><topic>Humans</topic><topic>Male</topic><topic>Maze Learning - physiology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Transgenic</topic><topic>Neuroglia - immunology</topic><topic>Neuroglia - pathology</topic><topic>Neurons - immunology</topic><topic>Neurons - pathology</topic><topic>Peptide Fragments - metabolism</topic><topic>Plaque, Amyloid - immunology</topic><topic>Plaque, Amyloid - pathology</topic><topic>Plaque, Amyloid - psychology</topic><topic>Receptor, Interferon alpha-beta - deficiency</topic><topic>Receptor, Interferon alpha-beta - genetics</topic><topic>Spatial Memory - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Minter, Myles R</creatorcontrib><creatorcontrib>Moore, Zachery</creatorcontrib><creatorcontrib>Zhang, Moses</creatorcontrib><creatorcontrib>Brody, Kate M</creatorcontrib><creatorcontrib>Jones, Nigel C</creatorcontrib><creatorcontrib>Shultz, Sandy R</creatorcontrib><creatorcontrib>Taylor, Juliet M</creatorcontrib><creatorcontrib>Crack, Peter J</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>PubMed Central (Full Participant titles)</collection><jtitle>Acta neuropathologica communications</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Minter, Myles R</au><au>Moore, Zachery</au><au>Zhang, Moses</au><au>Brody, Kate M</au><au>Jones, Nigel C</au><au>Shultz, Sandy R</au><au>Taylor, Juliet M</au><au>Crack, Peter J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Deletion of the type-1 interferon receptor in APPSWE/PS1ΔE9 mice preserves cognitive function and alters glial phenotype</atitle><jtitle>Acta neuropathologica communications</jtitle><addtitle>Acta Neuropathol Commun</addtitle><date>2016-07-11</date><risdate>2016</risdate><volume>4</volume><issue>1</issue><spage>72</spage><epage>72</epage><pages>72-72</pages><artnum>72</artnum><issn>2051-5960</issn><eissn>2051-5960</eissn><abstract>A neuro-inflammatory response is evident in Alzheimer's disease (AD), yet the precise mechanisms by which neuro-inflammation influences the progression of Alzheimer's disease (AD) remain poorly understood. Type-1 interferons (IFNs) are master regulators of innate immunity and have been implicated in multiple CNS disorders, however their role in AD progression has not yet been fully investigated. Hence, we generated APPSWE/PS1ΔE9 mice lacking the type-1 IFN alpha receptor-1 (IFNAR1, APPSWE/PS1ΔE9 x IFNAR1(-/-)) aged to 9 months to investigate the role of type-1 IFN signaling in a well-validated model of AD. APPSWE/PS1ΔE9 x IFNAR1(-/-) mice displayed a modest reduction in Aβ monomer levels, despite maintenance of plaque deposition. This finding correlated with partial rescue of spatial learning and memory impairments in the Morris water maze in comparison to APPSWE/PS1ΔE9 mice. Q-PCR identified a reduced type-1 IFN response and modulated pro-inflammatory cytokine secretion in APPSWE/PS1ΔE9 x IFNAR1(-/-) mice compared to APPSWE/PS1ΔE9 mice. Interestingly, immunohistochemistry displayed enhanced astrocyte reactivity but attenuated microgliosis surrounding amyloid plaque deposits in APPSWE/PS1ΔE9 x IFNAR1(-/-) mice in comparison to APPSWE/PS1ΔE9 mice. These APPSWE/PS1ΔE9 x IFNAR1(-/-) microglial populations demonstrated an anti-inflammatory phenotype that was confirmed in vitro by soluble Aβ1-42 treatment of IFNAR1(-/-) primary glial cultures. Our findings suggest that modulating neuro-inflammatory responses by suppressing type-1 IFN signaling may provide therapeutic benefit in AD.</abstract><cop>England</cop><pub>BioMed Central</pub><pmid>27400725</pmid><doi>10.1186/s40478-016-0341-4</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; SpringerLink Journals; PubMed Central Open Access; Springer Nature OA Free Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Alzheimer Disease - immunology Alzheimer Disease - pathology Alzheimer Disease - psychology Amyloid beta-Peptides - metabolism Animals Cells, Cultured Cerebral Cortex - immunology Cerebral Cortex - pathology Cognition - physiology Disease Models, Animal Female Gliosis - immunology Gliosis - pathology Gliosis - psychology Hippocampus - immunology Hippocampus - pathology Humans Male Maze Learning - physiology Mice Mice, Inbred C57BL Mice, Transgenic Neuroglia - immunology Neuroglia - pathology Neurons - immunology Neurons - pathology Peptide Fragments - metabolism Plaque, Amyloid - immunology Plaque, Amyloid - pathology Plaque, Amyloid - psychology Receptor, Interferon alpha-beta - deficiency Receptor, Interferon alpha-beta - genetics Spatial Memory - physiology |
| title | Deletion of the type-1 interferon receptor in APPSWE/PS1ΔE9 mice preserves cognitive function and alters glial phenotype |
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