Chronic Apocynin Treatment Attenuates Beta Amyloid Plaque Size and Microglial Number in hAPP(751)SL Mice
Background NADPH oxidase is implicated in neurotoxic microglial activation and the progressive nature of Alzheimer's Disease (AD). Here, we test the ability of two NADPH oxidase inhibitors, apocynin and dextromethorphan (DM), to reduce learning deficits and neuropathology in transgenic mice ove...
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| description | Background NADPH oxidase is implicated in neurotoxic microglial activation and the progressive nature of Alzheimer's Disease (AD). Here, we test the ability of two NADPH oxidase inhibitors, apocynin and dextromethorphan (DM), to reduce learning deficits and neuropathology in transgenic mice overexpressing human amyloid precursor protein with the Swedish and London mutations (hAPP(751)SL). Methods Four month old hAPP(751)SL mice were treated daily with saline, 15 mg/kg DM, 7.5 mg/kg DM, or 10 mg/kg apocynin by gavage for four months. Results Only hAPP(751)SL mice treated with apocynin showed reduced plaque size and a reduction in the number of cortical microglia, when compared to the saline treated group. Analysis of whole brain homogenates from all treatments tested (saline, DM, and apocynin) demonstrated low levels of TNFα, protein nitration, lipid peroxidation, and NADPH oxidase activation, indicating a low level of neuroinflammation and oxidative stress in hAPP(751)SL mice at 8 months of age that was not significantly affected by any drug treatment. Despite in vitro analyses demonstrating that apocynin and DM ameliorate Aβ-induced extracellular superoxide production and neurotoxicity, both DM and apocynin failed to significantly affect learning and memory tasks or synaptic density in hAPP(751)SL mice. To discern how apocynin was affecting plaque levels (plaque load) and microglial number in vivo, in vitro analysis of microglia was performed, revealing no apocynin effects on beta-amyloid (Aβ) phagocytosis, microglial proliferation, or microglial survival. Conclusions Together, this study suggests that while hAPP(751)SL mice show increases in microglial number and plaque load, they fail to exhibit elevated markers of neuroinflammation consistent with AD at 8 months of age, which may be a limitation of this animal model. Despite absence of clear neuroinflammation, apocynin was still able to reduce both plaque size and microglial number, suggesting that apocynin may have additional therapeutic effects independent of anti-inflammatory characteristics. |
| doi_str_mv | 10.1371/journal.pone.0020153 |
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Here, we test the ability of two NADPH oxidase inhibitors, apocynin and dextromethorphan (DM), to reduce learning deficits and neuropathology in transgenic mice overexpressing human amyloid precursor protein with the Swedish and London mutations (hAPP(751)SL). Methods Four month old hAPP(751)SL mice were treated daily with saline, 15 mg/kg DM, 7.5 mg/kg DM, or 10 mg/kg apocynin by gavage for four months. Results Only hAPP(751)SL mice treated with apocynin showed reduced plaque size and a reduction in the number of cortical microglia, when compared to the saline treated group. Analysis of whole brain homogenates from all treatments tested (saline, DM, and apocynin) demonstrated low levels of TNFα, protein nitration, lipid peroxidation, and NADPH oxidase activation, indicating a low level of neuroinflammation and oxidative stress in hAPP(751)SL mice at 8 months of age that was not significantly affected by any drug treatment. Despite in vitro analyses demonstrating that apocynin and DM ameliorate Aβ-induced extracellular superoxide production and neurotoxicity, both DM and apocynin failed to significantly affect learning and memory tasks or synaptic density in hAPP(751)SL mice. To discern how apocynin was affecting plaque levels (plaque load) and microglial number in vivo, in vitro analysis of microglia was performed, revealing no apocynin effects on beta-amyloid (Aβ) phagocytosis, microglial proliferation, or microglial survival. Conclusions Together, this study suggests that while hAPP(751)SL mice show increases in microglial number and plaque load, they fail to exhibit elevated markers of neuroinflammation consistent with AD at 8 months of age, which may be a limitation of this animal model. Despite absence of clear neuroinflammation, apocynin was still able to reduce both plaque size and microglial number, suggesting that apocynin may have additional therapeutic effects independent of anti-inflammatory characteristics.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0020153</identifier><identifier>PMID: 21655287</identifier><language>eng</language><publisher>San Francisco: Public Library of Science</publisher><subject>Activation ; Alzheimer's disease ; Amyloid precursor protein ; Animal cognition ; Animal models ; Biology ; Brain ; Cognitive ability ; Cortex ; Dextromethorphan ; Enzymes ; Hypoxia ; In vivo methods and tests ; Inflammation ; Learning ; Lipid peroxidation ; Low level ; Medicine ; Memory ; Memory tasks ; Mental task performance ; Mice ; Microglia ; Mutation ; NAD(P)H oxidase ; Neurobiology ; Neurodegenerative diseases ; Neurosciences ; Neurotoxicity ; Nitration ; Oxidase ; Oxidative stress ; Parkinson's disease ; Pathology ; Peroxidation ; Phagocytosis ; Rodents ; Superoxide ; Synaptic density ; Transgenic animals ; Transgenic mice ; Tumor necrosis factor-α ; β-Amyloid</subject><ispartof>PloS one, 2011-05, Vol.6 (5), p.e20153</ispartof><rights>2011 Lull et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Lull et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3853-eb41719e2f8d4febcb482e3c2b0d8f1057c763f0e38539c7bd3beb7b8fbbd63b3</citedby><cites>FETCH-LOGICAL-c3853-eb41719e2f8d4febcb482e3c2b0d8f1057c763f0e38539c7bd3beb7b8fbbd63b3</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/PMC3105011/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3105011/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids></links><search><contributor>Ginsberg, Stephen D.</contributor><creatorcontrib>Lull, Melinda E.</creatorcontrib><creatorcontrib>Levesque, Shannon</creatorcontrib><creatorcontrib>Surace, Michael J.</creatorcontrib><creatorcontrib>Block, Michelle L.</creatorcontrib><title>Chronic Apocynin Treatment Attenuates Beta Amyloid Plaque Size and Microglial Number in hAPP(751)SL Mice</title><title>PloS one</title><description>Background NADPH oxidase is implicated in neurotoxic microglial activation and the progressive nature of Alzheimer's Disease (AD). Here, we test the ability of two NADPH oxidase inhibitors, apocynin and dextromethorphan (DM), to reduce learning deficits and neuropathology in transgenic mice overexpressing human amyloid precursor protein with the Swedish and London mutations (hAPP(751)SL). Methods Four month old hAPP(751)SL mice were treated daily with saline, 15 mg/kg DM, 7.5 mg/kg DM, or 10 mg/kg apocynin by gavage for four months. Results Only hAPP(751)SL mice treated with apocynin showed reduced plaque size and a reduction in the number of cortical microglia, when compared to the saline treated group. Analysis of whole brain homogenates from all treatments tested (saline, DM, and apocynin) demonstrated low levels of TNFα, protein nitration, lipid peroxidation, and NADPH oxidase activation, indicating a low level of neuroinflammation and oxidative stress in hAPP(751)SL mice at 8 months of age that was not significantly affected by any drug treatment. Despite in vitro analyses demonstrating that apocynin and DM ameliorate Aβ-induced extracellular superoxide production and neurotoxicity, both DM and apocynin failed to significantly affect learning and memory tasks or synaptic density in hAPP(751)SL mice. To discern how apocynin was affecting plaque levels (plaque load) and microglial number in vivo, in vitro analysis of microglia was performed, revealing no apocynin effects on beta-amyloid (Aβ) phagocytosis, microglial proliferation, or microglial survival. Conclusions Together, this study suggests that while hAPP(751)SL mice show increases in microglial number and plaque load, they fail to exhibit elevated markers of neuroinflammation consistent with AD at 8 months of age, which may be a limitation of this animal model. Despite absence of clear neuroinflammation, apocynin was still able to reduce both plaque size and microglial number, suggesting that apocynin may have additional therapeutic effects independent of anti-inflammatory characteristics.</description><subject>Activation</subject><subject>Alzheimer's disease</subject><subject>Amyloid precursor protein</subject><subject>Animal cognition</subject><subject>Animal models</subject><subject>Biology</subject><subject>Brain</subject><subject>Cognitive ability</subject><subject>Cortex</subject><subject>Dextromethorphan</subject><subject>Enzymes</subject><subject>Hypoxia</subject><subject>In vivo methods and tests</subject><subject>Inflammation</subject><subject>Learning</subject><subject>Lipid peroxidation</subject><subject>Low level</subject><subject>Medicine</subject><subject>Memory</subject><subject>Memory tasks</subject><subject>Mental task performance</subject><subject>Mice</subject><subject>Microglia</subject><subject>Mutation</subject><subject>NAD(P)H oxidase</subject><subject>Neurobiology</subject><subject>Neurodegenerative diseases</subject><subject>Neurosciences</subject><subject>Neurotoxicity</subject><subject>Nitration</subject><subject>Oxidase</subject><subject>Oxidative stress</subject><subject>Parkinson's disease</subject><subject>Pathology</subject><subject>Peroxidation</subject><subject>Phagocytosis</subject><subject>Rodents</subject><subject>Superoxide</subject><subject>Synaptic density</subject><subject>Transgenic animals</subject><subject>Transgenic mice</subject><subject>Tumor necrosis factor-α</subject><subject>β-Amyloid</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1kUtLAzEUhYMoPqr_QDDgRhetecyrG2EsvqBqwboOSeZOG5lJajIj1F_vFEfRhasbuCfncL-D0DElI8pTevHqWm9lNVo5CyNCGKEx30L7dMzZMGGEb_9676GDEF4JiXmWJLtoj9EkjlmW7qPlZOmdNRrnK6fX1lg89yCbGmyD86YB28oGAr6CRuK8XlfOFHhWybcW8LP5ACxtgR-M9m5RGVnhx7ZW4HFns8xns7M0pufP040ADtFOKasAR_0coJeb6_nkbjh9ur2f5NOh5lnMh6AimtIxsDIrohKUVlHGgGumSJGVlMSpThNeEtioxzpVBVegUpWVShUJV3yATr58V5ULoocUBGXjjLMk6iAN0GWvaFUNhe5O9bISK29q6dfCSSP-bqxZioV7F7yLJ5R2Bqe9gXcdiND8ExN9qTo4IXgofxIoEZsGv3-JTYOib5B_AqtLkIA</recordid><startdate>20110531</startdate><enddate>20110531</enddate><creator>Lull, Melinda E.</creator><creator>Levesque, 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Apocynin Treatment Attenuates Beta Amyloid Plaque Size and Microglial Number in hAPP(751)SL Mice</title><author>Lull, Melinda E. ; Levesque, Shannon ; Surace, Michael J. ; Block, Michelle L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3853-eb41719e2f8d4febcb482e3c2b0d8f1057c763f0e38539c7bd3beb7b8fbbd63b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Activation</topic><topic>Alzheimer's disease</topic><topic>Amyloid precursor protein</topic><topic>Animal cognition</topic><topic>Animal models</topic><topic>Biology</topic><topic>Brain</topic><topic>Cognitive ability</topic><topic>Cortex</topic><topic>Dextromethorphan</topic><topic>Enzymes</topic><topic>Hypoxia</topic><topic>In vivo methods and tests</topic><topic>Inflammation</topic><topic>Learning</topic><topic>Lipid peroxidation</topic><topic>Low 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Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lull, Melinda E.</au><au>Levesque, Shannon</au><au>Surace, Michael J.</au><au>Block, Michelle L.</au><au>Ginsberg, Stephen D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Chronic Apocynin Treatment Attenuates Beta Amyloid Plaque Size and Microglial Number in hAPP(751)SL Mice</atitle><jtitle>PloS one</jtitle><date>2011-05-31</date><risdate>2011</risdate><volume>6</volume><issue>5</issue><spage>e20153</spage><pages>e20153-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Background NADPH oxidase is implicated in neurotoxic microglial activation and the progressive nature of Alzheimer's Disease (AD). Here, we test the ability of two NADPH oxidase inhibitors, apocynin and dextromethorphan (DM), to reduce learning deficits and neuropathology in transgenic mice overexpressing human amyloid precursor protein with the Swedish and London mutations (hAPP(751)SL). Methods Four month old hAPP(751)SL mice were treated daily with saline, 15 mg/kg DM, 7.5 mg/kg DM, or 10 mg/kg apocynin by gavage for four months. Results Only hAPP(751)SL mice treated with apocynin showed reduced plaque size and a reduction in the number of cortical microglia, when compared to the saline treated group. Analysis of whole brain homogenates from all treatments tested (saline, DM, and apocynin) demonstrated low levels of TNFα, protein nitration, lipid peroxidation, and NADPH oxidase activation, indicating a low level of neuroinflammation and oxidative stress in hAPP(751)SL mice at 8 months of age that was not significantly affected by any drug treatment. Despite in vitro analyses demonstrating that apocynin and DM ameliorate Aβ-induced extracellular superoxide production and neurotoxicity, both DM and apocynin failed to significantly affect learning and memory tasks or synaptic density in hAPP(751)SL mice. To discern how apocynin was affecting plaque levels (plaque load) and microglial number in vivo, in vitro analysis of microglia was performed, revealing no apocynin effects on beta-amyloid (Aβ) phagocytosis, microglial proliferation, or microglial survival. Conclusions Together, this study suggests that while hAPP(751)SL mice show increases in microglial number and plaque load, they fail to exhibit elevated markers of neuroinflammation consistent with AD at 8 months of age, which may be a limitation of this animal model. Despite absence of clear neuroinflammation, apocynin was still able to reduce both plaque size and microglial number, suggesting that apocynin may have additional therapeutic effects independent of anti-inflammatory characteristics.</abstract><cop>San Francisco</cop><pub>Public Library of Science</pub><pmid>21655287</pmid><doi>10.1371/journal.pone.0020153</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Activation Alzheimer's disease Amyloid precursor protein Animal cognition Animal models Biology Brain Cognitive ability Cortex Dextromethorphan Enzymes Hypoxia In vivo methods and tests Inflammation Learning Lipid peroxidation Low level Medicine Memory Memory tasks Mental task performance Mice Microglia Mutation NAD(P)H oxidase Neurobiology Neurodegenerative diseases Neurosciences Neurotoxicity Nitration Oxidase Oxidative stress Parkinson's disease Pathology Peroxidation Phagocytosis Rodents Superoxide Synaptic density Transgenic animals Transgenic mice Tumor necrosis factor-α β-Amyloid |
| title | Chronic Apocynin Treatment Attenuates Beta Amyloid Plaque Size and Microglial Number in hAPP(751)SL Mice |
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