Toll-Like Receptor Expression in the Blood and Brain of Patients and a Mouse Model of Parkinson’s Disease
Identifieur interne : 000488 ( Main/Exploration ); précédent : 000487; suivant : 000489Toll-Like Receptor Expression in the Blood and Brain of Patients and a Mouse Model of Parkinson’s Disease
Auteurs : Janelle Drouin-Ouellet ; Isabelle St-Amour ; Martine Saint-Pierre ; Jérôme Lamontagne-Proulx ; Jasna Kriz ; Roger A. Barker ; Francesca CicchettiSource :
- International Journal of Neuropsychopharmacology [ 1461-1457 ] ; 2015.
English descriptors
- KwdEn :
- Aged, Aged, 80 and over, Animals, Antiparkinson Agents (pharmacology), B-Lymphocytes (metabolism), Brain (drug effects), Brain (immunology), Brain (metabolism), Case-Control Studies, Dexamethasone (pharmacology), Disease Models, Animal, Female, Green Fluorescent Proteins (genetics), Green Fluorescent Proteins (metabolism), Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Microglia (drug effects), Microglia (metabolism), Middle Aged, Monocytes (metabolism), Parkinson Disease (blood), Parkinson Disease (drug therapy), Parkinson Disease (genetics), Parkinson Disease (immunology), Parkinson Disease (metabolism), Time Factors, Toll-Like Receptor 2 (metabolism), Toll-Like Receptor 4 (metabolism), Toll-Like Receptors (blood), Toll-Like Receptors (immunology), Toll-Like Receptors (metabolism), Up-Regulation, alpha-Synuclein (genetics), alpha-Synuclein (metabolism).
- MESH :
- chemical , blood : Toll-Like Receptors.
- chemical , genetics : Green Fluorescent Proteins, alpha-Synuclein.
- chemical , immunology : Toll-Like Receptors.
- chemical , metabolism : Green Fluorescent Proteins, Toll-Like Receptor 2, Toll-Like Receptor 4, Toll-Like Receptors, alpha-Synuclein.
- chemical , pharmacology : Antiparkinson Agents, Dexamethasone.
- blood : Parkinson Disease.
- drug effects : Brain, Microglia.
- drug therapy : Parkinson Disease.
- genetics : Parkinson Disease.
- immunology : Brain, Parkinson Disease.
- metabolism : B-Lymphocytes, Brain, Microglia, Monocytes, Parkinson Disease.
- Aged, Aged, 80 and over, Animals, Case-Control Studies, Disease Models, Animal, Female, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Time Factors, Up-Regulation.
Abstract
Accumulating evidence supports a role for the immune system in the pathogenesis of Parkinson’s disease. Importantly, recent preclinical studies are now suggesting a specific contribution of inflammation to the α-synuclein-induced pathology seen in this condition.
We used flow cytometry and western blots to detect toll-like receptor 2 and 4 expression in blood and brain samples of Parkinson’s disease patients and mice overexpressing human α-synuclein. To further assess the effects of α-synuclein overexpression on the innate immune system, we performed a longitudinal study using Thy1.2-α-synuclein mice that expressed a bicistronic DNA construct (reporter genes luciferase and green fluorescent protein) under the transcriptional control of the murine toll-like receptor 2 promoter.
Here, we report increases in toll-like receptors 2 and 4 expression in circulating monocytes and of toll-like receptor 4 in B cells and in the caudate/putamen of Parkinson’s disease patients. Monthly bioluminescence imaging of Thy1.2-α-synuclein mice showed increasing toll-like receptor 2 expression from 10 months of age, although no change in toll-like receptor 2 and 4 expression was observed in the blood and brain of these mice at 12 months of age. Dexamethasone treatment starting at 5 months of age for 1 month significantly decreased the microglial response in the brain of these mice and promoted functional recovery as observed using a wheel-running activity test.
Our results show that toll-like receptors 2 and 4 are modulated in the blood and brain of Parkinson’s disease patients and that overexpression of α-synuclein leads to a progressive microglial response, the inhibition of which has a beneficial impact on some motor phenotypes of an animal model of α-synucleinopathy.
Url:
DOI: 10.1093/ijnp/pyu103
PubMed: 25522431
PubMed Central: 4438545
Affiliations:
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Le document en format XML
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Barker</name></author><author><name sortKey="Cicchetti, Francesca" sort="Cicchetti, Francesca" uniqKey="Cicchetti F" first="Francesca" last="Cicchetti">Francesca Cicchetti</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25522431</idno><idno type="pmc">4438545</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4438545</idno><idno type="RBID">PMC:4438545</idno><idno type="doi">10.1093/ijnp/pyu103</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000065</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000065</idno><idno type="wicri:Area/Pmc/Curation">000065</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000065</idno><idno type="wicri:Area/Pmc/Checkpoint">000188</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000188</idno><idno type="wicri:source">PubMed</idno><idno type="wicri:Area/PubMed/Corpus">000624</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000624</idno><idno type="wicri:Area/PubMed/Curation">000624</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000624</idno><idno type="wicri:Area/PubMed/Checkpoint">000624</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000624</idno><idno type="wicri:Area/Ncbi/Merge">001A06</idno><idno type="wicri:Area/Ncbi/Curation">001A06</idno><idno type="wicri:Area/Ncbi/Checkpoint">001A06</idno><idno type="wicri:doubleKey">1461-1457:2015:Drouin Ouellet J:toll:like:receptor</idno><idno type="wicri:Area/Main/Merge">000489</idno><idno type="wicri:Area/Main/Curation">000488</idno><idno type="wicri:Area/Main/Exploration">000488</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Toll-Like Receptor Expression in the Blood and Brain of Patients and a Mouse Model of Parkinson’s Disease</title><author><name sortKey="Drouin Ouellet, Janelle" sort="Drouin Ouellet, Janelle" uniqKey="Drouin Ouellet J" first="Janelle" last="Drouin-Ouellet">Janelle Drouin-Ouellet</name></author><author><name sortKey="St Amour, Isabelle" sort="St Amour, Isabelle" uniqKey="St Amour I" first="Isabelle" last="St-Amour">Isabelle St-Amour</name></author><author><name sortKey="Saint Pierre, Martine" sort="Saint Pierre, Martine" uniqKey="Saint Pierre M" first="Martine" last="Saint-Pierre">Martine Saint-Pierre</name></author><author><name sortKey="Lamontagne Proulx, Jerome" sort="Lamontagne Proulx, Jerome" uniqKey="Lamontagne Proulx J" first="Jérôme" last="Lamontagne-Proulx">Jérôme Lamontagne-Proulx</name></author><author><name sortKey="Kriz, Jasna" sort="Kriz, Jasna" uniqKey="Kriz J" first="Jasna" last="Kriz">Jasna Kriz</name></author><author><name sortKey="Barker, Roger A" sort="Barker, Roger A" uniqKey="Barker R" first="Roger A." last="Barker">Roger A. Barker</name></author><author><name sortKey="Cicchetti, Francesca" sort="Cicchetti, Francesca" uniqKey="Cicchetti F" first="Francesca" last="Cicchetti">Francesca Cicchetti</name></author></analytic><series><title level="j">International Journal of Neuropsychopharmacology</title><idno type="ISSN">1461-1457</idno><idno type="eISSN">1469-5111</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Aged</term><term>Aged, 80 and over</term><term>Animals</term><term>Antiparkinson Agents (pharmacology)</term><term>B-Lymphocytes (metabolism)</term><term>Brain (drug effects)</term><term>Brain (immunology)</term><term>Brain (metabolism)</term><term>Case-Control Studies</term><term>Dexamethasone (pharmacology)</term><term>Disease Models, Animal</term><term>Female</term><term>Green Fluorescent Proteins (genetics)</term><term>Green Fluorescent Proteins (metabolism)</term><term>Humans</term><term>Male</term><term>Mice, Inbred C57BL</term><term>Mice, Transgenic</term><term>Microglia (drug effects)</term><term>Microglia (metabolism)</term><term>Middle Aged</term><term>Monocytes (metabolism)</term><term>Parkinson Disease (blood)</term><term>Parkinson Disease (drug therapy)</term><term>Parkinson Disease (genetics)</term><term>Parkinson Disease (immunology)</term><term>Parkinson Disease (metabolism)</term><term>Time Factors</term><term>Toll-Like Receptor 2 (metabolism)</term><term>Toll-Like Receptor 4 (metabolism)</term><term>Toll-Like Receptors (blood)</term><term>Toll-Like Receptors (immunology)</term><term>Toll-Like Receptors (metabolism)</term><term>Up-Regulation</term><term>alpha-Synuclein (genetics)</term><term>alpha-Synuclein (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="blood" xml:lang="en"><term>Toll-Like Receptors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Green Fluorescent Proteins</term><term>alpha-Synuclein</term></keywords><keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Toll-Like Receptors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Green Fluorescent Proteins</term><term>Toll-Like Receptor 2</term><term>Toll-Like Receptor 4</term><term>Toll-Like Receptors</term><term>alpha-Synuclein</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiparkinson Agents</term><term>Dexamethasone</term></keywords><keywords scheme="MESH" qualifier="blood" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Brain</term><term>Microglia</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Brain</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>B-Lymphocytes</term><term>Brain</term><term>Microglia</term><term>Monocytes</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Aged</term><term>Aged, 80 and over</term><term>Animals</term><term>Case-Control Studies</term><term>Disease Models, Animal</term><term>Female</term><term>Humans</term><term>Male</term><term>Mice, Inbred C57BL</term><term>Mice, Transgenic</term><term>Middle Aged</term><term>Time Factors</term><term>Up-Regulation</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background:</title><p>Accumulating evidence supports a role for the immune system in the pathogenesis of Parkinson’s disease. Importantly, recent preclinical studies are now suggesting a specific contribution of inflammation to the α-synuclein-induced pathology seen in this condition.</p></sec><sec><title>Methods:</title><p>We used flow cytometry and western blots to detect toll-like receptor 2 and 4 expression in blood and brain samples of Parkinson’s disease patients and mice overexpressing human α-synuclein. To further assess the effects of α-synuclein overexpression on the innate immune system, we performed a longitudinal study using Thy1.2-α-synuclein mice that expressed a bicistronic DNA construct (reporter genes luciferase and green fluorescent protein) under the transcriptional control of the murine toll-like receptor 2 promoter.</p></sec><sec><title>Results:</title><p>Here, we report increases in toll-like receptors 2 and 4 expression in circulating monocytes and of toll-like receptor 4 in B cells and in the caudate/putamen of Parkinson’s disease patients. Monthly bioluminescence imaging of Thy1.2-α-synuclein mice showed increasing toll-like receptor 2 expression from 10 months of age, although no change in toll-like receptor 2 and 4 expression was observed in the blood and brain of these mice at 12 months of age. Dexamethasone treatment starting at 5 months of age for 1 month significantly decreased the microglial response in the brain of these mice and promoted functional recovery as observed using a wheel-running activity test.</p></sec><sec><title>Conclusion:</title><p>Our results show that toll-like receptors 2 and 4 are modulated in the blood and brain of Parkinson’s disease patients and that overexpression of α-synuclein leads to a progressive microglial response, the inhibition of which has a beneficial impact on some motor phenotypes of an animal model of α-synucleinopathy.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Anderson, Dc" uniqKey="Anderson D">DC Anderson</name></author><author><name sortKey="Cranford, Re" uniqKey="Cranford R">RE Cranford</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Baba, Y" uniqKey="Baba Y">Y Baba</name></author><author><name sortKey="Kuroiwa, A" 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Wu</name></author><author><name sortKey="Masliah, E" uniqKey="Masliah E">E Masliah</name></author><author><name sortKey="Effros, Rb" uniqKey="Effros R">RB Effros</name></author><author><name sortKey="Chesselet, Mf" uniqKey="Chesselet M">MF Chesselet</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="West, Ap" uniqKey="West A">AP West</name></author><author><name sortKey="Koblansky, Aa" uniqKey="Koblansky A">AA Koblansky</name></author><author><name sortKey="Ghosh, S" uniqKey="Ghosh S">S Ghosh</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhang, W" uniqKey="Zhang W">W Zhang</name></author><author><name sortKey="Wang, T" uniqKey="Wang T">T Wang</name></author><author><name sortKey="Pei, Z" uniqKey="Pei Z">Z Pei</name></author><author><name sortKey="Miller, Ds" uniqKey="Miller D">DS Miller</name></author><author><name sortKey="Wu, X" uniqKey="Wu X">X Wu</name></author><author><name sortKey="Block, Ml" uniqKey="Block M">ML Block</name></author><author><name sortKey="Wilson, B" uniqKey="Wilson B">B Wilson</name></author><author><name sortKey="Zhang, W" uniqKey="Zhang W">W Zhang</name></author><author><name sortKey="Zhou, Y" uniqKey="Zhou Y">Y Zhou</name></author><author><name sortKey="Hong, Js" uniqKey="Hong J">JS Hong</name></author><author><name sortKey="Zhang, J" uniqKey="Zhang J">J Zhang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ziegler Heitbrock, L" uniqKey="Ziegler Heitbrock L">L Ziegler-Heitbrock</name></author><author><name sortKey="Hofer, Tp" uniqKey="Hofer T">TP Hofer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ziegler Heitbrock, Hw" uniqKey="Ziegler Heitbrock H">HW Ziegler-Heitbrock</name></author><author><name sortKey="Appl, B" uniqKey="Appl B">B Appl</name></author><author><name sortKey="Kafferlein, E" uniqKey="Kafferlein E">E Kafferlein</name></author><author><name sortKey="Loffler, T" uniqKey="Loffler T">T Loffler</name></author><author><name sortKey="Jahn Henninger, H" uniqKey="Jahn Henninger H">H Jahn-Henninger</name></author><author><name sortKey="Gutensohn, W" uniqKey="Gutensohn W">W Gutensohn</name></author><author><name sortKey="Nores, Jr" uniqKey="Nores J">JR Nores</name></author><author><name sortKey="Mccullough, K" uniqKey="Mccullough K">K McCullough</name></author><author><name sortKey="Passlick, B" uniqKey="Passlick B">B Passlick</name></author><author><name sortKey="Labeta, Mo" uniqKey="Labeta M">MO Labeta</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list></list><tree><noCountry><name sortKey="Barker, Roger A" sort="Barker, Roger A" uniqKey="Barker R" first="Roger A." last="Barker">Roger A. Barker</name><name sortKey="Cicchetti, Francesca" sort="Cicchetti, Francesca" uniqKey="Cicchetti F" first="Francesca" last="Cicchetti">Francesca Cicchetti</name><name sortKey="Drouin Ouellet, Janelle" sort="Drouin Ouellet, Janelle" uniqKey="Drouin Ouellet J" first="Janelle" last="Drouin-Ouellet">Janelle Drouin-Ouellet</name><name sortKey="Kriz, Jasna" sort="Kriz, Jasna" uniqKey="Kriz J" first="Jasna" last="Kriz">Jasna Kriz</name><name sortKey="Lamontagne Proulx, Jerome" sort="Lamontagne Proulx, Jerome" uniqKey="Lamontagne Proulx J" first="Jérôme" last="Lamontagne-Proulx">Jérôme Lamontagne-Proulx</name><name sortKey="Saint Pierre, Martine" sort="Saint Pierre, Martine" uniqKey="Saint Pierre M" first="Martine" last="Saint-Pierre">Martine Saint-Pierre</name><name sortKey="St Amour, Isabelle" sort="St Amour, Isabelle" uniqKey="St Amour I" first="Isabelle" last="St-Amour">Isabelle St-Amour</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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