Modulação do sistema das poliaminas e bloqueio seletivo de correntes de K+ do tipo A reverte o dano cognitivo induzido por peptídeo β-amiloide25-35
Autor(a) principal: | |
---|---|
Data de Publicação: | 2013 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Manancial - Repositório Digital da UFSM |
Texto Completo: | http://repositorio.ufsm.br/handle/1/4483 |
Resumo: | In Alzheimer s disease (AD), β-amyloid peptide (Aβ) has been linked with synaptic loss and cognitive dysfunction, albeit the precise mechanism remains unknown. An involvement of N-Methyl-D-Aspartate receptors (NMDAR) in AD is proposed, since its inhibition attenuates some aspects of AD s neuropathology. In this regard, polyamines, like spermidine and spermine, positive modulators of NMDARs, have been shown to have both concentration and synthesis increased by Aβ. Using the novel object recognition task we showed that negative modulation of polyamine system, been trough blockade of its binding site at NMDAR by arcaine (0.02 nmol/site), traxoprodil (0.002 nmol/site), or inhibition of polyamine synthesis by DFMO (2.7 nmol/site), reverses Aβ25-35-induced memory impairment in mice. The activation of polyamine binding site at NMDAR located at extrasynaptic sites might underlie the cognitive deficits of Aβ25-35-treated mice, since incubation of hippocampal neuron cultures with spermidine (400 μM) or Aβ25-35 (10 μM) significantly increased nuclear accumulation of jacob protein, a marker of extrasynaptic NMDAR activation. Moreover, traxoprodil (4nM), arcaine (4 μM) or DFMO (5 μM) blocked the Aβ-induced jacob nuclear translocation. Activation of extrasynaptic NMDAR in neurons leads to striping of synaptic contacts and simplification of neuronal cytoarchitecture. Incubation of hippocampal neuron cultures with traxoprodil (4 Nm), arcaine (4 μM) or DFMO (5 μM) reversed the deleterious effects of Aβ25-35 on dendritic spine number and spine morphology. We also evaluated the involvement of A-type K+ currents on the Aβ25-35-induced memory impairment. Administration of Tx3-1 (3 100 pmol/site), a selective IA blocker, restored memory of mice injected with Aβ25-35 and tested on the novel object recognition task The reversal of memory impairment and the protective effect on dendritic spine alterations exerted by the modulators of the polyamine system suggest the polyamine binding site at extrasynaptic NMDAR a potential player in Aβ-induced cognitive deficit. |
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2015-10-162015-10-162013-11-18GOMES, Guilherme Monteiro. MODULATION OF POLYAMINE SYSTEM AND BLOCKADE OF A-TYPE K+ CURRENTS COUNTERACTS β-AMYLOID25-35-INDUCED COGNITIVE DEFICITS. 2013. 125 f. Tese (Doutorado em Ciências Biológicas) - Universidade Federal de Santa Maria, Santa Maria, 2013.http://repositorio.ufsm.br/handle/1/4483In Alzheimer s disease (AD), β-amyloid peptide (Aβ) has been linked with synaptic loss and cognitive dysfunction, albeit the precise mechanism remains unknown. An involvement of N-Methyl-D-Aspartate receptors (NMDAR) in AD is proposed, since its inhibition attenuates some aspects of AD s neuropathology. In this regard, polyamines, like spermidine and spermine, positive modulators of NMDARs, have been shown to have both concentration and synthesis increased by Aβ. Using the novel object recognition task we showed that negative modulation of polyamine system, been trough blockade of its binding site at NMDAR by arcaine (0.02 nmol/site), traxoprodil (0.002 nmol/site), or inhibition of polyamine synthesis by DFMO (2.7 nmol/site), reverses Aβ25-35-induced memory impairment in mice. The activation of polyamine binding site at NMDAR located at extrasynaptic sites might underlie the cognitive deficits of Aβ25-35-treated mice, since incubation of hippocampal neuron cultures with spermidine (400 μM) or Aβ25-35 (10 μM) significantly increased nuclear accumulation of jacob protein, a marker of extrasynaptic NMDAR activation. Moreover, traxoprodil (4nM), arcaine (4 μM) or DFMO (5 μM) blocked the Aβ-induced jacob nuclear translocation. Activation of extrasynaptic NMDAR in neurons leads to striping of synaptic contacts and simplification of neuronal cytoarchitecture. Incubation of hippocampal neuron cultures with traxoprodil (4 Nm), arcaine (4 μM) or DFMO (5 μM) reversed the deleterious effects of Aβ25-35 on dendritic spine number and spine morphology. We also evaluated the involvement of A-type K+ currents on the Aβ25-35-induced memory impairment. Administration of Tx3-1 (3 100 pmol/site), a selective IA blocker, restored memory of mice injected with Aβ25-35 and tested on the novel object recognition task The reversal of memory impairment and the protective effect on dendritic spine alterations exerted by the modulators of the polyamine system suggest the polyamine binding site at extrasynaptic NMDAR a potential player in Aβ-induced cognitive deficit.O peptídeo β-amiloide (Aβ), reconhecido como agente tóxico na Doença de Alzheimer (DA) é implicado como causador de danos cognitivos e sinápticos, apesar de os mecanismos não serem completamente compreendidos. O envolvimento do receptor N-metil-D-aspartato (NMDA) na DA é sugerido, visto que o seu bloqueio atenua alguns aspectos neuropatológicos da DA. Nesse contexto, tem sido demonstrado que as poliaminas, como espermidina e espermina, moduladores positivos do receptor NMDA, possuem níveis e síntese elevada tanto no cérebro de pacientes com DA como em preparações in vitro utilizando o peptídeo Aβ. Neste estudo demonstrou-se que a modulação do sistema das poliaminas, através do bloqueio do seu sítio de ligação no receptor NMDA por arcaína (0,02 nmol/sítio), traxoprodil (0,002 nmol/sítio) ou da inibição de sua síntese por DFMO (2,7 nmol/sítio), reverte o déficit cognitivo induzido pela injeção de Aβ25-35 em camundongos testados na tarefa de reconhecimento de objetos. A ativação do sítio de ligação das poliaminas em receptores NMDA extrassinápticos pode subjazer o déficit cognitivo de camundongos injetados com Aβ25-35, visto que a incubação de culturas primárias de neurônios hipocampais com espermidina (400 μM), NMDA (200 μM) ou Aβ25-35 (10 μM) aumenta o acúmulo nuclear de jacob, um marcador de ativação de receptores NMDA extrassinápticos, de maneira significante. Ademais, traxoprodil (4 nM), arcaína (4 μM) ou DFMO (5 μM) bloquearam o acúmulo nuclear de jacob induzido por Aβ. A ativação de receptores NMDA extrassinápticos em neurônios leva a simplificação da citoarquitetura neuronal e a diminuição de contatos sinápticos. Aqui demonstrou-se que a incubação de culturas de neurônios hipocampais com traxoprodil (4 nM), arcaína (4 μM) ou DFMO (5 μM) reverte as alterações na a densidade e morfologia de espinhas dendríticas induzido pela incubação com Aβ25-35. Ainda, também avaliou-se o envolvimento de correntes de K+ do tipo A no déficit cognitivo induzido pela injeção i.c.v. de Aβ25-35. A administração de Tx3-1 (3 100 pmol/sítio), um bloqueador seletivo de correntes IA, reverteu o prejuízo de memória de camundongos injetados com Aβ25-35 e testados na tarefa de reconhecimento de objetos. A reversão dos danos cognitivos e sinápticos induzidos por Aβ25-35 através da modulação do sistema das poliaminas sugere a estimulação do sítio de ligação das poliaminas no receptor NMDA, possivelmente extrassínaptico, como um dos mecanimos por trás do déficit cognitivo induzido pelo peptídeo Aβ.Conselho Nacional de Desenvolvimento Científico e Tecnológicoapplication/pdfporUniversidade Federal de Santa MariaPrograma de Pós-Graduação em Ciências Biológicas: Bioquímica ToxicológicaUFSMBRBioquímicaPoliaminasMemóriaReceptor NMDA extrassinápticoReconhecimento de objetosEspermidinaTraxoprodilArcaínaDFMOPoliaminesMemoryExtrasynaptic NMDA receptorsβ-amiloid peptideNovel object recognition taskSpermidineArcaineCNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICAModulação do sistema das poliaminas e bloqueio seletivo de correntes de K+ do tipo A reverte o dano cognitivo induzido por peptídeo β-amiloide25-35Modulation of polyamine system and blockade of A-Type K+ currents counteracts β-Amyloid25-35-induced cognitive deficitsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisRubin, Maribel Antonellohttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4794806H7Porciúncula, Lisiane de Oliveirahttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4795444H9#BancasFachinetto, Roseleihttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4755373E2Oliveira, Mauro Schneiderhttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4705848A9Royes, Luiz Fernando Freirehttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4705849Y0http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4248785U5Gomes, Guilherme Monteiro20080000000240050030030050030050017f72a93-232f-40b3-9c14-1b54b978789b30cbc093-3a28-4e5e-b2ef-1916a18d954d85c9bd88-7da3-4393-a0c5-9940b096dc8e6a615e4f-285a-4d77-aeb6-a33cd9c07f80df67a9a8-bb2b-4fe4-b1ab-0baffdb61ead606a5885-4038-438d-8b9d-cec2378006a1info:eu-repo/semantics/openAccessreponame:Manancial - Repositório Digital da UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSMORIGINALGOMES, GUILHERME MONTEIRO.pdfapplication/pdf4450799http://repositorio.ufsm.br/bitstream/1/4483/1/GOMES%2c%20GUILHERME%20MONTEIRO.pdfe8342bbd0d6bccc29d2d7a5d90921477MD51TEXTGOMES, GUILHERME MONTEIRO.pdf.txtGOMES, GUILHERME MONTEIRO.pdf.txtExtracted texttext/plain195242http://repositorio.ufsm.br/bitstream/1/4483/2/GOMES%2c%20GUILHERME%20MONTEIRO.pdf.txt4288744697bd392ec2dcef0262f6159eMD52THUMBNAILGOMES, GUILHERME MONTEIRO.pdf.jpgGOMES, GUILHERME MONTEIRO.pdf.jpgIM Thumbnailimage/jpeg5008http://repositorio.ufsm.br/bitstream/1/4483/3/GOMES%2c%20GUILHERME%20MONTEIRO.pdf.jpg752034f91db5f0107385ed81296a39c7MD531/44832017-07-30 00:50:17.433oai:repositorio.ufsm.br:1/4483Repositório Institucionalhttp://repositorio.ufsm.br/PUBhttp://repositorio.ufsm.br/oai/requestopendoar:39132017-07-30T03:50:17Manancial - Repositório Digital da UFSM - Universidade Federal de Santa Maria (UFSM)false |
dc.title.por.fl_str_mv |
Modulação do sistema das poliaminas e bloqueio seletivo de correntes de K+ do tipo A reverte o dano cognitivo induzido por peptídeo β-amiloide25-35 |
dc.title.alternative.eng.fl_str_mv |
Modulation of polyamine system and blockade of A-Type K+ currents counteracts β-Amyloid25-35-induced cognitive deficits |
title |
Modulação do sistema das poliaminas e bloqueio seletivo de correntes de K+ do tipo A reverte o dano cognitivo induzido por peptídeo β-amiloide25-35 |
spellingShingle |
Modulação do sistema das poliaminas e bloqueio seletivo de correntes de K+ do tipo A reverte o dano cognitivo induzido por peptídeo β-amiloide25-35 Gomes, Guilherme Monteiro Poliaminas Memória Receptor NMDA extrassináptico Reconhecimento de objetos Espermidina Traxoprodil Arcaína DFMO Poliamines Memory Extrasynaptic NMDA receptors β-amiloid peptide Novel object recognition task Spermidine Arcaine CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
title_short |
Modulação do sistema das poliaminas e bloqueio seletivo de correntes de K+ do tipo A reverte o dano cognitivo induzido por peptídeo β-amiloide25-35 |
title_full |
Modulação do sistema das poliaminas e bloqueio seletivo de correntes de K+ do tipo A reverte o dano cognitivo induzido por peptídeo β-amiloide25-35 |
title_fullStr |
Modulação do sistema das poliaminas e bloqueio seletivo de correntes de K+ do tipo A reverte o dano cognitivo induzido por peptídeo β-amiloide25-35 |
title_full_unstemmed |
Modulação do sistema das poliaminas e bloqueio seletivo de correntes de K+ do tipo A reverte o dano cognitivo induzido por peptídeo β-amiloide25-35 |
title_sort |
Modulação do sistema das poliaminas e bloqueio seletivo de correntes de K+ do tipo A reverte o dano cognitivo induzido por peptídeo β-amiloide25-35 |
author |
Gomes, Guilherme Monteiro |
author_facet |
Gomes, Guilherme Monteiro |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Rubin, Maribel Antonello |
dc.contributor.advisor1Lattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4794806H7 |
dc.contributor.referee1.fl_str_mv |
Porciúncula, Lisiane de Oliveira |
dc.contributor.referee1Lattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4795444H9#Bancas |
dc.contributor.referee2.fl_str_mv |
Fachinetto, Roselei |
dc.contributor.referee2Lattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4755373E2 |
dc.contributor.referee3.fl_str_mv |
Oliveira, Mauro Schneider |
dc.contributor.referee3Lattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4705848A9 |
dc.contributor.referee4.fl_str_mv |
Royes, Luiz Fernando Freire |
dc.contributor.referee4Lattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4705849Y0 |
dc.contributor.authorLattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4248785U5 |
dc.contributor.author.fl_str_mv |
Gomes, Guilherme Monteiro |
contributor_str_mv |
Rubin, Maribel Antonello Porciúncula, Lisiane de Oliveira Fachinetto, Roselei Oliveira, Mauro Schneider Royes, Luiz Fernando Freire |
dc.subject.por.fl_str_mv |
Poliaminas Memória Receptor NMDA extrassináptico Reconhecimento de objetos Espermidina Traxoprodil Arcaína DFMO |
topic |
Poliaminas Memória Receptor NMDA extrassináptico Reconhecimento de objetos Espermidina Traxoprodil Arcaína DFMO Poliamines Memory Extrasynaptic NMDA receptors β-amiloid peptide Novel object recognition task Spermidine Arcaine CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
dc.subject.eng.fl_str_mv |
Poliamines Memory Extrasynaptic NMDA receptors β-amiloid peptide Novel object recognition task Spermidine Arcaine |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA |
description |
In Alzheimer s disease (AD), β-amyloid peptide (Aβ) has been linked with synaptic loss and cognitive dysfunction, albeit the precise mechanism remains unknown. An involvement of N-Methyl-D-Aspartate receptors (NMDAR) in AD is proposed, since its inhibition attenuates some aspects of AD s neuropathology. In this regard, polyamines, like spermidine and spermine, positive modulators of NMDARs, have been shown to have both concentration and synthesis increased by Aβ. Using the novel object recognition task we showed that negative modulation of polyamine system, been trough blockade of its binding site at NMDAR by arcaine (0.02 nmol/site), traxoprodil (0.002 nmol/site), or inhibition of polyamine synthesis by DFMO (2.7 nmol/site), reverses Aβ25-35-induced memory impairment in mice. The activation of polyamine binding site at NMDAR located at extrasynaptic sites might underlie the cognitive deficits of Aβ25-35-treated mice, since incubation of hippocampal neuron cultures with spermidine (400 μM) or Aβ25-35 (10 μM) significantly increased nuclear accumulation of jacob protein, a marker of extrasynaptic NMDAR activation. Moreover, traxoprodil (4nM), arcaine (4 μM) or DFMO (5 μM) blocked the Aβ-induced jacob nuclear translocation. Activation of extrasynaptic NMDAR in neurons leads to striping of synaptic contacts and simplification of neuronal cytoarchitecture. Incubation of hippocampal neuron cultures with traxoprodil (4 Nm), arcaine (4 μM) or DFMO (5 μM) reversed the deleterious effects of Aβ25-35 on dendritic spine number and spine morphology. We also evaluated the involvement of A-type K+ currents on the Aβ25-35-induced memory impairment. Administration of Tx3-1 (3 100 pmol/site), a selective IA blocker, restored memory of mice injected with Aβ25-35 and tested on the novel object recognition task The reversal of memory impairment and the protective effect on dendritic spine alterations exerted by the modulators of the polyamine system suggest the polyamine binding site at extrasynaptic NMDAR a potential player in Aβ-induced cognitive deficit. |
publishDate |
2013 |
dc.date.issued.fl_str_mv |
2013-11-18 |
dc.date.accessioned.fl_str_mv |
2015-10-16 |
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2015-10-16 |
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info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
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doctoralThesis |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
GOMES, Guilherme Monteiro. MODULATION OF POLYAMINE SYSTEM AND BLOCKADE OF A-TYPE K+ CURRENTS COUNTERACTS β-AMYLOID25-35-INDUCED COGNITIVE DEFICITS. 2013. 125 f. Tese (Doutorado em Ciências Biológicas) - Universidade Federal de Santa Maria, Santa Maria, 2013. |
dc.identifier.uri.fl_str_mv |
http://repositorio.ufsm.br/handle/1/4483 |
identifier_str_mv |
GOMES, Guilherme Monteiro. MODULATION OF POLYAMINE SYSTEM AND BLOCKADE OF A-TYPE K+ CURRENTS COUNTERACTS β-AMYLOID25-35-INDUCED COGNITIVE DEFICITS. 2013. 125 f. Tese (Doutorado em Ciências Biológicas) - Universidade Federal de Santa Maria, Santa Maria, 2013. |
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http://repositorio.ufsm.br/handle/1/4483 |
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por |
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