Publicação
Amyloid-β peptide impairs BDNF effects upon GABA release from rat synaptosomes in a calpain dependent way
| Resumo: | Alzheimer's disease (AD) affects neural networks, which involves multiple changes in hippocampal GABAergic transmission. While the cause of AD is uncertain, several lines of evidence suggest amyloid-β (Aβ) peptides as having a causal role in this pathogenesis. It has been shown that brain-derived neurotrophic factor (BDNF) inhibits K+-evoked gamma-aminobutyric acid (GABA) release, but the effect of the exposure to Aβ peptides on BDNF-induced GABA release inhibition has not yet been elucidated. On the other hand, it is known that BDNF levels are decreased in AD, and Aβ peptide decreases BDNF receptor, tyrosine kinase B receptor (TrkB), levels by a calpain-dependent mechanism. In this work it was evaluated the role of Aβ peptide upon BDNF effects on K+-evoked GABA release from rat hippocampal synaptosomes prepared from hippocampal slices incubated with Aβ25-35 (25μM) or Aβ1-42 (20μM) or without Aβ. It was also studied the involvement of calpains inhibition on the Aβ peptide impairment of the BDNF effect upon GABA release by incubating hippocampal slices with Aβ and MDL28170 (20μM), an inhibitor of calpains.The results showed that the incubation of hippocampal slices with Aβ25-35 (25M) or Aβ1-42 (20μM) does not alter S2/S1 ratio for GABA K+-evoked release. In hippocampal slices incubated with Aβ25-35 (25 M) or Aβ1-42 (20μM) the inhibitory effect of BDNF upon GABA release was totally abolished. Calpain inhibition with MDL28170 (20μM) allowed the completely recovery of the BDNF inhibitory effect in Aβ25-35 (25 M) presence.With this work we describe for the first time the impairment of BDNF inhibitory effect, on the evoked-GABA release, mediated by Aβ peptides. This impairment involves a mechanism dependent on calpain activation, since the inhibition of calpains completely recover the BDNF effect in presence of Aβ peptides. Thus the present work highlights a new mechanism involved in the Aβ-induced TrkB dysregulation, and supports the use of calpain inhibitors as a therapeutic tool in AD. |
|---|---|
| Autores principais: | Lérias, Sofia Ramos Rapaz |
| Assunto: | Amyloid-β GABA Brain-derived neurotrophic factor (BDNF) Calpains |
| Ano: | 2014 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso restrito |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Alzheimer's disease (AD) affects neural networks, which involves multiple changes in hippocampal GABAergic transmission. While the cause of AD is uncertain, several lines of evidence suggest amyloid-β (Aβ) peptides as having a causal role in this pathogenesis. It has been shown that brain-derived neurotrophic factor (BDNF) inhibits K+-evoked gamma-aminobutyric acid (GABA) release, but the effect of the exposure to Aβ peptides on BDNF-induced GABA release inhibition has not yet been elucidated. On the other hand, it is known that BDNF levels are decreased in AD, and Aβ peptide decreases BDNF receptor, tyrosine kinase B receptor (TrkB), levels by a calpain-dependent mechanism. In this work it was evaluated the role of Aβ peptide upon BDNF effects on K+-evoked GABA release from rat hippocampal synaptosomes prepared from hippocampal slices incubated with Aβ25-35 (25μM) or Aβ1-42 (20μM) or without Aβ. It was also studied the involvement of calpains inhibition on the Aβ peptide impairment of the BDNF effect upon GABA release by incubating hippocampal slices with Aβ and MDL28170 (20μM), an inhibitor of calpains.The results showed that the incubation of hippocampal slices with Aβ25-35 (25M) or Aβ1-42 (20μM) does not alter S2/S1 ratio for GABA K+-evoked release. In hippocampal slices incubated with Aβ25-35 (25 M) or Aβ1-42 (20μM) the inhibitory effect of BDNF upon GABA release was totally abolished. Calpain inhibition with MDL28170 (20μM) allowed the completely recovery of the BDNF inhibitory effect in Aβ25-35 (25 M) presence.With this work we describe for the first time the impairment of BDNF inhibitory effect, on the evoked-GABA release, mediated by Aβ peptides. This impairment involves a mechanism dependent on calpain activation, since the inhibition of calpains completely recover the BDNF effect in presence of Aβ peptides. Thus the present work highlights a new mechanism involved in the Aβ-induced TrkB dysregulation, and supports the use of calpain inhibitors as a therapeutic tool in AD. |
|---|