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InfluĂȘncia dos receptores A2a da adenosina no efeito neuroprotector do BDNF na morte neuronal induzida
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O factor neurotrĂłfico derivado do cĂ©rebro (BDNF) Ă© uma neurotrofina que promove sobrevivĂȘncia neuronal atravĂ©s da activação do seu receptor TrkB. Na doença de Alzheimer ocorre deposição do pĂ©ptido AÎČ (amyloid-beta) e consequente morte neuronal. Dado que os nĂveis de BDNF se encontram diminuĂdos nesta doença, a administração directa desta neurotrofina ao cĂ©rebro tem sido sugerida como terapĂȘutica. Contudo esta abordagem revelou-se difĂcil de implementar pelo que sĂŁo necessĂĄrias alternativas, como por exemplo, o uso de pequenas molĂ©culas que potenciem os efeitos do BDNF endĂłgeno no cĂ©rebro. Ă sabido que o receptor A2A da adenosina pode trans-activar os receptores TrkB na ausĂȘncia de BDNF. Do ponto de vista funcional, sabe-se que os efeitos desta neurotrofina na transmissĂŁo sinĂĄptica e plasticidade sinĂĄptica sĂŁo dependentes da activação do receptor A2A. Assim, na presente dissertação, pretendeu-se avaliar a influĂȘncia dos receptores A2A no efeito neuroprotector do BDNF na morte neuronal induzida pelo pĂ©ptido AÎČ, e tambĂ©m, analisar o efeito deste pĂ©ptido nos nĂveis dos receptores TrkB. Os resultados mostram que o BDNF diminui a morte neuronal por apoptose induzida pelo pĂ©ptido AÎČ, e que essa protecção Ă© superior em culturas primĂĄrias de neurĂłnios com 10 DIV (days in-vitro) do que com 4 DIV.Por outro lado, a activação do receptor A2A da adenosina, em culturas com 4 DIV, bloqueou o efeito protector do BDNF. Contudo, em culturas com 10 DIV, o efeito protector do BDNF nĂŁo Ă© influenciado pela activação do receptor A2A. Em ambas as culturas (4 e 10 DIV) a activação do receptor A2A, por si sĂł, nĂŁo altera os nĂveis de apoptose induzida pelo AÎČ. Durante a presente dissertação tambĂ©m se observou que o pĂ©ptido AÎČ provoca uma diminuição na isoforma completa do receptor TrkB concomitante com um aumento na isoforma truncada do receptor. Este aumento na isoforma truncada Ă© dependente da sĂntese proteica e Ă© prevenido pela administração exĂłgena de BDNF. Em conclusĂŁo, os resultados sugerem que o pĂ©ptido AÎČ poderĂĄ reduzir a neuroprotecção endĂłgena exercida pelo BDNF devido Ă s alteraçÔes nas isoformas do receptor TrkB, e que a activação dos receptores A2A de adenosina pode diminuir o efeito protector do BDNF na apoptose induzida pelo pĂ©ptido AÎČ.
Brain-derived neurotrophic factor (BDNF) is a neurotrophin which promotes neuronal survival through activation of TrkB receptor. In Alzheimerâs disease (AD), the deposition of amyloid-beta peptide (AÎČ) contributes to neuronal death. Since the levels of BDNF are reduced in this disorder, direct administration of this neurotrophin into the brain was considered a promising therapeutic approach. It is, however, not simple and therefore, new approaches, like the use of small molecules which can potentiate the endogenous BDNF effects in the brain, were proposed. It is known that adenosine A2A receptors can trans-activate TrkB receptors even in the absence of BNDF. In a functional point of view, the effects of BDNF in synaptic plasticity and transmission are dependent of A2A receptors activation. The objective in this work was to evaluate the influence of A2A receptors upon BDNF neuroprotective effect against neuronal death induced by AÎČ peptide, and also, to analyse the effect of this peptide in the levels of TrkB receptor. The results obtained show that BDNF reduces neuronal apoptotic death induced by AÎČ, and that this neuroprotection is more pronounced in 10 days in-vitro primary neuronal cultures (10DIV) than in 4 DIV cultures. On the other hand, in 4 DIV cells, A2A receptors activation blocked the protective effect of BDNF. However, in 10 DIV cultures, A2A receptors activation did not influence the BDNF-induced neuroprotection. In both cultures (4 and 10 DIV), the activation of A2A receptors did not changed the apoptosis levels induced by AÎČ peptide. In the present work it was also observed that AÎČ peptide administration produced a decrease in the full length isoform of TrkB receptor concomitantly with an increase in the truncated isoform of TrkB receptor. This increase in truncated receptor is dependent on protein synthesis and was prevented if BDNF was added to the cultures. In conclusion, these results suggest that AÎČ peptide can reduce neuroprotection caused by endogenous BDNF because it induces TrkB isoform changes, and that the BDNF-induced protection against neuronal death can be diminished by activation of adenosine A2A receptor.
Brain-derived neurotrophic factor (BDNF) is a neurotrophin which promotes neuronal survival through activation of TrkB receptor. In Alzheimerâs disease (AD), the deposition of amyloid-beta peptide (AÎČ) contributes to neuronal death. Since the levels of BDNF are reduced in this disorder, direct administration of this neurotrophin into the brain was considered a promising therapeutic approach. It is, however, not simple and therefore, new approaches, like the use of small molecules which can potentiate the endogenous BDNF effects in the brain, were proposed. It is known that adenosine A2A receptors can trans-activate TrkB receptors even in the absence of BNDF. In a functional point of view, the effects of BDNF in synaptic plasticity and transmission are dependent of A2A receptors activation. The objective in this work was to evaluate the influence of A2A receptors upon BDNF neuroprotective effect against neuronal death induced by AÎČ peptide, and also, to analyse the effect of this peptide in the levels of TrkB receptor. The results obtained show that BDNF reduces neuronal apoptotic death induced by AÎČ, and that this neuroprotection is more pronounced in 10 days in-vitro primary neuronal cultures (10DIV) than in 4 DIV cultures. On the other hand, in 4 DIV cells, A2A receptors activation blocked the protective effect of BDNF. However, in 10 DIV cultures, A2A receptors activation did not influence the BDNF-induced neuroprotection. In both cultures (4 and 10 DIV), the activation of A2A receptors did not changed the apoptosis levels induced by AÎČ peptide. In the present work it was also observed that AÎČ peptide administration produced a decrease in the full length isoform of TrkB receptor concomitantly with an increase in the truncated isoform of TrkB receptor. This increase in truncated receptor is dependent on protein synthesis and was prevented if BDNF was added to the cultures. In conclusion, these results suggest that AÎČ peptide can reduce neuroprotection caused by endogenous BDNF because it induces TrkB isoform changes, and that the BDNF-induced protection against neuronal death can be diminished by activation of adenosine A2A receptor.
Descrição
Tese de mestrado, BioquĂmica (BioquĂmica MĂ©dica), Universidade de Lisboa, Faculdade de CiĂȘncias, 2009
Palavras-chave
Adenosina Apoptose BDNF Culturas de neurĂłnios Neuroprotecção PĂ©ptido ÎČ amilĂłide Receptor A2A Receptor TrkB Teses de mestrado - 2009