Papel do receptor B2 de cininas na patogênese e progressão da doença de Alzheimer experimental: da resposta imune à cognição
Autor(a) principal: | |
---|---|
Data de Publicação: | 2019 |
Tipo de documento: | Dissertação |
Idioma: | por |
Título da fonte: | Biblioteca Digital de Teses e Dissertações do UFSM |
Texto Completo: | http://repositorio.ufsm.br/handle/1/19455 |
Resumo: | Alzheimer's disease (AD) is a complex and progressive neurodegenerative disorder characterized by the decline and loss of cognitive functions, and it is the most common of dementias. The major pathological features of AD are the presence of amyloid plaques which consist of aggregates of amyloid beta peptide (Aβ) and neurofibrillary tangles formed mainly by hyperphosphorylated tau proteins. Among several factors that are involved in the pathogenesis and progression of AD, neuroinflammation is an inherent process in the pathogenesis of AD. Studies show that the kinin system is stimulated by the pathological Aβ in AD patients. The effects of this system are mainly mediated by bradykinin (BK) and its kinin- B2 receptor (B2R) and include the direct action of blood-brain barrier (BBB) permeabilization and inflammation. Thus, we investigated the possible effects of B2R blockade on different AD models: double transgenic male mice (n = 6 to 8) as a family AD model (APPswe / PS1dE9) and oligomeric Aβ peptide injections in C57BL6 males (n = 10), expressing B2R or not and pretreated with saline or B2R antagonist: HOE-140. Acetylcholinesterase levels and BBB permeability were verified after injection with β-amyloid oligomer (AβOS). In addition, object recognition testing was performed on animals aged 3, 6 and 9 months for APPswe / PS1dE9 genotype and 48 hours and 7 days on animals injected with AβOS. The data obtained show the first evidence that AβOS increased BHE permeability and HOE-140 provided significant protection against AβOS effect. Similarly, the B2R antagonist reduced acetylcholinesterase (AchE) activity, suggesting that B2R modulation may act as a new therapeutic strategy for AD, already used clinically to treat hereditary angioedema. Interestingly, both HOE-140 and B2R knockout (B2R-/-) prevented long-term memory decline in AD models. Collectively, these results suggest that B2R blockade may be a target of prophylactic treatment in neurodegeneration deceleration. |
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2020-01-31T13:32:54Z2020-01-31T13:32:54Z2019-08-02http://repositorio.ufsm.br/handle/1/19455Alzheimer's disease (AD) is a complex and progressive neurodegenerative disorder characterized by the decline and loss of cognitive functions, and it is the most common of dementias. The major pathological features of AD are the presence of amyloid plaques which consist of aggregates of amyloid beta peptide (Aβ) and neurofibrillary tangles formed mainly by hyperphosphorylated tau proteins. Among several factors that are involved in the pathogenesis and progression of AD, neuroinflammation is an inherent process in the pathogenesis of AD. Studies show that the kinin system is stimulated by the pathological Aβ in AD patients. The effects of this system are mainly mediated by bradykinin (BK) and its kinin- B2 receptor (B2R) and include the direct action of blood-brain barrier (BBB) permeabilization and inflammation. Thus, we investigated the possible effects of B2R blockade on different AD models: double transgenic male mice (n = 6 to 8) as a family AD model (APPswe / PS1dE9) and oligomeric Aβ peptide injections in C57BL6 males (n = 10), expressing B2R or not and pretreated with saline or B2R antagonist: HOE-140. Acetylcholinesterase levels and BBB permeability were verified after injection with β-amyloid oligomer (AβOS). In addition, object recognition testing was performed on animals aged 3, 6 and 9 months for APPswe / PS1dE9 genotype and 48 hours and 7 days on animals injected with AβOS. The data obtained show the first evidence that AβOS increased BHE permeability and HOE-140 provided significant protection against AβOS effect. Similarly, the B2R antagonist reduced acetylcholinesterase (AchE) activity, suggesting that B2R modulation may act as a new therapeutic strategy for AD, already used clinically to treat hereditary angioedema. Interestingly, both HOE-140 and B2R knockout (B2R-/-) prevented long-term memory decline in AD models. Collectively, these results suggest that B2R blockade may be a target of prophylactic treatment in neurodegeneration deceleration.A doença de Alzheimer (DA) é uma doença neurodegenerativa complexa e progressiva caracterizada pelo declínio e perda das funções cognitivas, sendo a mais comum das demências. As principais características histopatológicas da DA são a presença de placas amilóides, compostas por agregados do peptídeo beta-amilóide (βA) e emaranhados neurofibrilares (ENFs) formados principalmente por proteínas tau hiperfosforiladas. Em meio a vários fatores que estão envolvidos na patogênese e progressão da DA, a neuroinflamação é um processo inerente à patogênese da doença de Alzheimer (DA). Estudos demonstram que o sistema de cininas é estimulado pelo peptídeo patológico βA em pacientes com DA. Os efeitos desse sistema são mediados principalmente pela bradicinina (BK) e seu receptor B2 de cininas (B2R) e compreendem a ação direta na permeabilização da barreira hematoencefálica (BHE) e na inflamação. Assim, investigamos os possíveis efeitos do bloqueio do B2R em diferentes modelos de DA: camundongos machos (n= 6 a 8) duplos transgênicos como modelo da DA familiar (APPswe / PS1dE9) e injeções de peptídeo βA oligomérico em machos C57BL6 (n=10), ambos expressando ou não B2R ou pré-tratados com antagonista de B2R: HOE-140. Atividade da acetilcolinesterase e a permeabilidade da BHE foram verificados após injeção com oligômero de β-amilóide (AβOs). Adicionalmente, testes de reconhecimento de objeto foram realizados em animais de 3, 6 e 9 meses para o genótipo APPswe/PS1dE9 e 48 horas e 7 dias em animais injetados com AβOs. Os dados obtidos mostram a primeira evidência de que os AβOs aumentaram a permeabilidade da BHE e o HOE-140 proporciona proteção significativa contra o efeito dos AβOs. Similarmente, o antagonista de B2R reduziu a atividade da acetilcolinesterase (AchE), sugerindo que a modulação de B2R pode atuar como uma nova estratégia terapêutica para a DA, já usada na clínica para tratar o angioedema hereditário. Curiosamente, tanto HOE-140 quanto o knockout genético de B2R (B2R-/-) impediram o declínio da memória de longo prazo nos camundongos modelos da DA. Coletivamente, estes resultados sugerem que o bloqueio de B2R pode ser um alvo de tratamento profilático na desaceleração da neurodegeneração.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESporUniversidade Federal de Santa MariaCentro de Ciências da SaúdePrograma de Pós-Graduação em FarmacologiaUFSMBrasilFarmacologiaAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessReceptor B2 de cininasCamundongos nocauteCamundongos APPswe/PS1dE9AcetilcolinesteraseKinin-B2 receptorKnockout miceAPPswe/PS1dE9 miceAcetylcholinesteraseCNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIAPapel do receptor B2 de cininas na patogênese e progressão da doença de Alzheimer experimental: da resposta imune à cogniçãoRole of kinin receptor B2 in the pathogenesis and progression of experimental Alzheimer disease: from immunity response to cognitioninfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisPillat, Micheli Mainardihttp://lattes.cnpq.br/5712882578120587Cappellari, Angélica Reginahttp://lattes.cnpq.br/4692188672005790Oliveira, Mauro Schneiderhttp://lattes.cnpq.br/7132934163734175http://lattes.cnpq.br/1396515434492600Viero, Fernanda Tibolla20100000000060041c70ae4-6782-4033-a587-1d79bc2955ad62b5e6d4-f30a-4db5-a10c-aa0c935dd899851f7b0c-a97a-46bb-ab89-d5f65d23edc9cf98ddcb-3930-42cf-9437-be60eebd8056reponame:Biblioteca Digital de Teses e Dissertações do UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSMORIGINALDIS_PPGFARMACOLOGIA_2019_VIERO_FERNANDA.pdfDIS_PPGFARMACOLOGIA_2019_VIERO_FERNANDA.pdfDissertação de Mestradoapplication/pdf1164362http://repositorio.ufsm.br/bitstream/1/19455/1/DIS_PPGFARMACOLOGIA_2019_VIERO_FERNANDA.pdf1d9eb5e255b939760f6f9a22eea02192MD51CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; 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dc.title.por.fl_str_mv |
Papel do receptor B2 de cininas na patogênese e progressão da doença de Alzheimer experimental: da resposta imune à cognição |
dc.title.alternative.eng.fl_str_mv |
Role of kinin receptor B2 in the pathogenesis and progression of experimental Alzheimer disease: from immunity response to cognition |
title |
Papel do receptor B2 de cininas na patogênese e progressão da doença de Alzheimer experimental: da resposta imune à cognição |
spellingShingle |
Papel do receptor B2 de cininas na patogênese e progressão da doença de Alzheimer experimental: da resposta imune à cognição Viero, Fernanda Tibolla Receptor B2 de cininas Camundongos nocaute Camundongos APPswe/PS1dE9 Acetilcolinesterase Kinin-B2 receptor Knockout mice APPswe/PS1dE9 mice Acetylcholinesterase CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
title_short |
Papel do receptor B2 de cininas na patogênese e progressão da doença de Alzheimer experimental: da resposta imune à cognição |
title_full |
Papel do receptor B2 de cininas na patogênese e progressão da doença de Alzheimer experimental: da resposta imune à cognição |
title_fullStr |
Papel do receptor B2 de cininas na patogênese e progressão da doença de Alzheimer experimental: da resposta imune à cognição |
title_full_unstemmed |
Papel do receptor B2 de cininas na patogênese e progressão da doença de Alzheimer experimental: da resposta imune à cognição |
title_sort |
Papel do receptor B2 de cininas na patogênese e progressão da doença de Alzheimer experimental: da resposta imune à cognição |
author |
Viero, Fernanda Tibolla |
author_facet |
Viero, Fernanda Tibolla |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Pillat, Micheli Mainardi |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/5712882578120587 |
dc.contributor.referee1.fl_str_mv |
Cappellari, Angélica Regina |
dc.contributor.referee1Lattes.fl_str_mv |
http://lattes.cnpq.br/4692188672005790 |
dc.contributor.referee2.fl_str_mv |
Oliveira, Mauro Schneider |
dc.contributor.referee2Lattes.fl_str_mv |
http://lattes.cnpq.br/7132934163734175 |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/1396515434492600 |
dc.contributor.author.fl_str_mv |
Viero, Fernanda Tibolla |
contributor_str_mv |
Pillat, Micheli Mainardi Cappellari, Angélica Regina Oliveira, Mauro Schneider |
dc.subject.por.fl_str_mv |
Receptor B2 de cininas Camundongos nocaute Camundongos APPswe/PS1dE9 Acetilcolinesterase |
topic |
Receptor B2 de cininas Camundongos nocaute Camundongos APPswe/PS1dE9 Acetilcolinesterase Kinin-B2 receptor Knockout mice APPswe/PS1dE9 mice Acetylcholinesterase CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
dc.subject.eng.fl_str_mv |
Kinin-B2 receptor Knockout mice APPswe/PS1dE9 mice Acetylcholinesterase |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
description |
Alzheimer's disease (AD) is a complex and progressive neurodegenerative disorder characterized by the decline and loss of cognitive functions, and it is the most common of dementias. The major pathological features of AD are the presence of amyloid plaques which consist of aggregates of amyloid beta peptide (Aβ) and neurofibrillary tangles formed mainly by hyperphosphorylated tau proteins. Among several factors that are involved in the pathogenesis and progression of AD, neuroinflammation is an inherent process in the pathogenesis of AD. Studies show that the kinin system is stimulated by the pathological Aβ in AD patients. The effects of this system are mainly mediated by bradykinin (BK) and its kinin- B2 receptor (B2R) and include the direct action of blood-brain barrier (BBB) permeabilization and inflammation. Thus, we investigated the possible effects of B2R blockade on different AD models: double transgenic male mice (n = 6 to 8) as a family AD model (APPswe / PS1dE9) and oligomeric Aβ peptide injections in C57BL6 males (n = 10), expressing B2R or not and pretreated with saline or B2R antagonist: HOE-140. Acetylcholinesterase levels and BBB permeability were verified after injection with β-amyloid oligomer (AβOS). In addition, object recognition testing was performed on animals aged 3, 6 and 9 months for APPswe / PS1dE9 genotype and 48 hours and 7 days on animals injected with AβOS. The data obtained show the first evidence that AβOS increased BHE permeability and HOE-140 provided significant protection against AβOS effect. Similarly, the B2R antagonist reduced acetylcholinesterase (AchE) activity, suggesting that B2R modulation may act as a new therapeutic strategy for AD, already used clinically to treat hereditary angioedema. Interestingly, both HOE-140 and B2R knockout (B2R-/-) prevented long-term memory decline in AD models. Collectively, these results suggest that B2R blockade may be a target of prophylactic treatment in neurodegeneration deceleration. |
publishDate |
2019 |
dc.date.issued.fl_str_mv |
2019-08-02 |
dc.date.accessioned.fl_str_mv |
2020-01-31T13:32:54Z |
dc.date.available.fl_str_mv |
2020-01-31T13:32:54Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
format |
masterThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://repositorio.ufsm.br/handle/1/19455 |
url |
http://repositorio.ufsm.br/handle/1/19455 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.relation.cnpq.fl_str_mv |
201000000000 |
dc.relation.confidence.fl_str_mv |
600 |
dc.relation.authority.fl_str_mv |
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dc.rights.driver.fl_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências da Saúde |
dc.publisher.program.fl_str_mv |
Programa de Pós-Graduação em Farmacologia |
dc.publisher.initials.fl_str_mv |
UFSM |
dc.publisher.country.fl_str_mv |
Brasil |
dc.publisher.department.fl_str_mv |
Farmacologia |
publisher.none.fl_str_mv |
Universidade Federal de Santa Maria Centro de Ciências da Saúde |
dc.source.none.fl_str_mv |
reponame:Biblioteca Digital de Teses e Dissertações do UFSM instname:Universidade Federal de Santa Maria (UFSM) instacron:UFSM |
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