Caffeine and adenosine A 2A receptor inactivation decrease striatal neuropathology in a lentiviral-based model of Machado–Joseph disease
Autor(a) principal: | |
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Data de Publicação: | 2013 |
Outros Autores: | , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10316/28116 |
Resumo: | Objective: Machado–Joseph disease (MJD) is a neurodegenerative disorder associated with an abnormal CAG expansion, which translates into an expanded polyglutamine tract within ataxin-3. There is no therapy to prevent or modify disease progression. Because caffeine (a nonselective adenosine receptor antagonist) and selective adenosine A2A receptor (A2A R) blockade alleviate neurodegeneration in different brain diseases, namely at early stages of another polyglutamine-related disorder such as Huntington’s disease, we now tested their ability to control MJD-associated neurodegeneration. Methods: MJD was modeled by transducing the striatum of male adult C57Bl/6 mice with lentiviral vectors encoding mutant ataxin-3 in one hemisphere and wild-type ataxin-3 in the other hemisphere (as internal control). Caffeine (1g/L) was applied through the drinking water. Mice were killed at different time points (from 2 to 12 weeks) to probe for the appearance of different morphological changes using immunohistochemical analysis. Results: Mutant ataxin-3 caused an evolving neuronal dysfunction (loss of DARPP-32 staining) leading to neurodegeneration (cresyl violet and neuronal nuclei staining) associated with increased number of mutant ataxin-3 inclusions in the basal ganglia. Notably, mutant ataxin-3 triggered early synaptotoxicity (decreased synaptophysin and microtubule-associated protein-2 staining) and reactive gliosis (glial fibrillary acidic protein and CD11b staining), which predated neuronal dysfunction and damage. Caffeine reduced the appearance of all these morphological modifications, which were also abrogated in mice with a global A2A R inactivation (knockout). Interpretation: Our findings provide a demonstration that synaptotoxicity and gliosis are precocious events in MJD and that caffeine and A2A R inactivation decrease MJD-associated striatal pathology, which paves the way to consider A2A Rs as novel therapeutic targets to manage MJD. |
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Caffeine and adenosine A 2A receptor inactivation decrease striatal neuropathology in a lentiviral-based model of Machado–Joseph diseaseMachado–Joseph diseaseCaffeineAdenosine A 2A receptorObjective: Machado–Joseph disease (MJD) is a neurodegenerative disorder associated with an abnormal CAG expansion, which translates into an expanded polyglutamine tract within ataxin-3. There is no therapy to prevent or modify disease progression. Because caffeine (a nonselective adenosine receptor antagonist) and selective adenosine A2A receptor (A2A R) blockade alleviate neurodegeneration in different brain diseases, namely at early stages of another polyglutamine-related disorder such as Huntington’s disease, we now tested their ability to control MJD-associated neurodegeneration. Methods: MJD was modeled by transducing the striatum of male adult C57Bl/6 mice with lentiviral vectors encoding mutant ataxin-3 in one hemisphere and wild-type ataxin-3 in the other hemisphere (as internal control). Caffeine (1g/L) was applied through the drinking water. Mice were killed at different time points (from 2 to 12 weeks) to probe for the appearance of different morphological changes using immunohistochemical analysis. Results: Mutant ataxin-3 caused an evolving neuronal dysfunction (loss of DARPP-32 staining) leading to neurodegeneration (cresyl violet and neuronal nuclei staining) associated with increased number of mutant ataxin-3 inclusions in the basal ganglia. Notably, mutant ataxin-3 triggered early synaptotoxicity (decreased synaptophysin and microtubule-associated protein-2 staining) and reactive gliosis (glial fibrillary acidic protein and CD11b staining), which predated neuronal dysfunction and damage. Caffeine reduced the appearance of all these morphological modifications, which were also abrogated in mice with a global A2A R inactivation (knockout). Interpretation: Our findings provide a demonstration that synaptotoxicity and gliosis are precocious events in MJD and that caffeine and A2A R inactivation decrease MJD-associated striatal pathology, which paves the way to consider A2A Rs as novel therapeutic targets to manage MJD.Wiley2013info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleGONÇALVES, Nélio; SIMÕES, Ana T; CUNHA, Rodrigo A; ALMEIDA, Luís Pereira de - Caffeine and adenosine A2A receptor inactivation decrease striatal neuropathology in a lentiviral-based model of Machado–Joseph disease. “Annals of Neurology”. ISSN: 0364-5134. 73 (2013) 655–666. Disponível na Internet em: <URL:http://hdl.handle.net/10316/28116>.http://hdl.handle.net/10316/28116GONÇALVES, Nélio; SIMÕES, Ana T; CUNHA, Rodrigo A; ALMEIDA, Luís Pereira de - Caffeine and adenosine A2A receptor inactivation decrease striatal neuropathology in a lentiviral-based model of Machado–Joseph disease. “Annals of Neurology”. ISSN: 0364-5134. 73 (2013) 655–666. Disponível na Internet em: <URL:http://hdl.handle.net/10316/28116>.http://hdl.handle.net/10316/28116eng0364-5134Gonçalves, NélioSimões, Ana T.Cunha, Rodrigo A.Almeida, Luís Pereira deinfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2020-05-29T09:42:27Zoai:estudogeral.uc.pt:10316/28116Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:47:29.080116Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Caffeine and adenosine A 2A receptor inactivation decrease striatal neuropathology in a lentiviral-based model of Machado–Joseph disease |
title |
Caffeine and adenosine A 2A receptor inactivation decrease striatal neuropathology in a lentiviral-based model of Machado–Joseph disease |
spellingShingle |
Caffeine and adenosine A 2A receptor inactivation decrease striatal neuropathology in a lentiviral-based model of Machado–Joseph disease Gonçalves, Nélio Machado–Joseph disease Caffeine Adenosine A 2A receptor |
title_short |
Caffeine and adenosine A 2A receptor inactivation decrease striatal neuropathology in a lentiviral-based model of Machado–Joseph disease |
title_full |
Caffeine and adenosine A 2A receptor inactivation decrease striatal neuropathology in a lentiviral-based model of Machado–Joseph disease |
title_fullStr |
Caffeine and adenosine A 2A receptor inactivation decrease striatal neuropathology in a lentiviral-based model of Machado–Joseph disease |
title_full_unstemmed |
Caffeine and adenosine A 2A receptor inactivation decrease striatal neuropathology in a lentiviral-based model of Machado–Joseph disease |
title_sort |
Caffeine and adenosine A 2A receptor inactivation decrease striatal neuropathology in a lentiviral-based model of Machado–Joseph disease |
author |
Gonçalves, Nélio |
author_facet |
Gonçalves, Nélio Simões, Ana T. Cunha, Rodrigo A. Almeida, Luís Pereira de |
author_role |
author |
author2 |
Simões, Ana T. Cunha, Rodrigo A. Almeida, Luís Pereira de |
author2_role |
author author author |
dc.contributor.author.fl_str_mv |
Gonçalves, Nélio Simões, Ana T. Cunha, Rodrigo A. Almeida, Luís Pereira de |
dc.subject.por.fl_str_mv |
Machado–Joseph disease Caffeine Adenosine A 2A receptor |
topic |
Machado–Joseph disease Caffeine Adenosine A 2A receptor |
description |
Objective: Machado–Joseph disease (MJD) is a neurodegenerative disorder associated with an abnormal CAG expansion, which translates into an expanded polyglutamine tract within ataxin-3. There is no therapy to prevent or modify disease progression. Because caffeine (a nonselective adenosine receptor antagonist) and selective adenosine A2A receptor (A2A R) blockade alleviate neurodegeneration in different brain diseases, namely at early stages of another polyglutamine-related disorder such as Huntington’s disease, we now tested their ability to control MJD-associated neurodegeneration. Methods: MJD was modeled by transducing the striatum of male adult C57Bl/6 mice with lentiviral vectors encoding mutant ataxin-3 in one hemisphere and wild-type ataxin-3 in the other hemisphere (as internal control). Caffeine (1g/L) was applied through the drinking water. Mice were killed at different time points (from 2 to 12 weeks) to probe for the appearance of different morphological changes using immunohistochemical analysis. Results: Mutant ataxin-3 caused an evolving neuronal dysfunction (loss of DARPP-32 staining) leading to neurodegeneration (cresyl violet and neuronal nuclei staining) associated with increased number of mutant ataxin-3 inclusions in the basal ganglia. Notably, mutant ataxin-3 triggered early synaptotoxicity (decreased synaptophysin and microtubule-associated protein-2 staining) and reactive gliosis (glial fibrillary acidic protein and CD11b staining), which predated neuronal dysfunction and damage. Caffeine reduced the appearance of all these morphological modifications, which were also abrogated in mice with a global A2A R inactivation (knockout). Interpretation: Our findings provide a demonstration that synaptotoxicity and gliosis are precocious events in MJD and that caffeine and A2A R inactivation decrease MJD-associated striatal pathology, which paves the way to consider A2A Rs as novel therapeutic targets to manage MJD. |
publishDate |
2013 |
dc.date.none.fl_str_mv |
2013 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
GONÇALVES, Nélio; SIMÕES, Ana T; CUNHA, Rodrigo A; ALMEIDA, Luís Pereira de - Caffeine and adenosine A2A receptor inactivation decrease striatal neuropathology in a lentiviral-based model of Machado–Joseph disease. “Annals of Neurology”. ISSN: 0364-5134. 73 (2013) 655–666. Disponível na Internet em: <URL:http://hdl.handle.net/10316/28116>. http://hdl.handle.net/10316/28116 GONÇALVES, Nélio; SIMÕES, Ana T; CUNHA, Rodrigo A; ALMEIDA, Luís Pereira de - Caffeine and adenosine A2A receptor inactivation decrease striatal neuropathology in a lentiviral-based model of Machado–Joseph disease. “Annals of Neurology”. ISSN: 0364-5134. 73 (2013) 655–666. Disponível na Internet em: <URL:http://hdl.handle.net/10316/28116>. http://hdl.handle.net/10316/28116 |
identifier_str_mv |
GONÇALVES, Nélio; SIMÕES, Ana T; CUNHA, Rodrigo A; ALMEIDA, Luís Pereira de - Caffeine and adenosine A2A receptor inactivation decrease striatal neuropathology in a lentiviral-based model of Machado–Joseph disease. “Annals of Neurology”. ISSN: 0364-5134. 73 (2013) 655–666. Disponível na Internet em: <URL:http://hdl.handle.net/10316/28116>. |
url |
http://hdl.handle.net/10316/28116 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
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0364-5134 |
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info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Wiley |
publisher.none.fl_str_mv |
Wiley |
dc.source.none.fl_str_mv |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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1799133752154128384 |