Publicação
Amyloid β peptide and p63 : two prime triggers of neural apoptosis and differentiation
| Resumo: | Amyloid β (Aβ) peptide accumulation and apoptosis play an important role in the pathogenesis of Alzheimer’s disease. However, the mechanisms by which Aβ mediates neuronal apoptosis are not completely elucidated. Mounting evidence also supports the involvement of specific apoptosis factors in neural stem cell (NSC) differentiation. Therefore, we set to identify and characterize new molecular pathways involved in Aβ-induced regulation of neural apoptosis and differentiation. First, we further explored the molecular mechanisms of Aβ-induced neuronal death. We found that Aβ elicited stabilization of the pro-apoptotic isoform of p63, TAp63, which in turn was partially inhibited by tauroursodeoxycholic acid. In addition, in response to Aβ-induced apoptosis, the abundance of the anti-apoptotic isoform of p63, ΔNp63, was clearly reduced and tightly regulated in a c-Jun-dependent mechanism. Next, we investigated whether apoptosis-associated molecule p63, member of the p53 family, might also be involved in differentiation of NSCs. We showed that TAp63γ interacted with the histone H3 lysine 27-specific demethylase JMJD3, a key regulator of neurogenesis, to redirect NSCs to differentiation, as an alternative to cell death. In addition, both TAp63γ and JMJD3 were coordinately regulated to establish a neural-specific gene expression pattern during NSC differentiation. We also found that JMJD3-demethylase activity was crucial in regulating TAp63γ half-life and nuclear accumulation. Finally, we evaluated the ability of Aβ peptides to modulate NSC proliferation and differentiation, and investigated whether autophagy was involved in Aβ-induced alterations of NSC fate. We showed that Aβ1-40 and Aβ1-42 strongly enhanced neurogenesis and gliogenesis, respectively, while Aβ25-35 did not influence NSC fate. Notably, autophagy was implicated in Aβ-mediated effects in NSCs, independently of reactive oxygen species production and apoptosis induction. In conclusion, the work presented here provides additional insights into the molecular mechanisms implicated in Aβ- and p63-induced cell death signaling pathways, and extends our knowledge in considering these prime triggers of apoptosis as integral components of neural proliferation and differentiation. |
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| Autores principais: | Fonseca, Maria Benedita Pereira de Vasconcelos, 1983- |
| Assunto: | Péptidos beta-amiloides Apoptose Autofagia Células-tronco neurais Neurogénese Teses de doutoramento - 2013 |
| Ano: | 2013 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Amyloid β (Aβ) peptide accumulation and apoptosis play an important role in the pathogenesis of Alzheimer’s disease. However, the mechanisms by which Aβ mediates neuronal apoptosis are not completely elucidated. Mounting evidence also supports the involvement of specific apoptosis factors in neural stem cell (NSC) differentiation. Therefore, we set to identify and characterize new molecular pathways involved in Aβ-induced regulation of neural apoptosis and differentiation. First, we further explored the molecular mechanisms of Aβ-induced neuronal death. We found that Aβ elicited stabilization of the pro-apoptotic isoform of p63, TAp63, which in turn was partially inhibited by tauroursodeoxycholic acid. In addition, in response to Aβ-induced apoptosis, the abundance of the anti-apoptotic isoform of p63, ΔNp63, was clearly reduced and tightly regulated in a c-Jun-dependent mechanism. Next, we investigated whether apoptosis-associated molecule p63, member of the p53 family, might also be involved in differentiation of NSCs. We showed that TAp63γ interacted with the histone H3 lysine 27-specific demethylase JMJD3, a key regulator of neurogenesis, to redirect NSCs to differentiation, as an alternative to cell death. In addition, both TAp63γ and JMJD3 were coordinately regulated to establish a neural-specific gene expression pattern during NSC differentiation. We also found that JMJD3-demethylase activity was crucial in regulating TAp63γ half-life and nuclear accumulation. Finally, we evaluated the ability of Aβ peptides to modulate NSC proliferation and differentiation, and investigated whether autophagy was involved in Aβ-induced alterations of NSC fate. We showed that Aβ1-40 and Aβ1-42 strongly enhanced neurogenesis and gliogenesis, respectively, while Aβ25-35 did not influence NSC fate. Notably, autophagy was implicated in Aβ-mediated effects in NSCs, independently of reactive oxygen species production and apoptosis induction. In conclusion, the work presented here provides additional insights into the molecular mechanisms implicated in Aβ- and p63-induced cell death signaling pathways, and extends our knowledge in considering these prime triggers of apoptosis as integral components of neural proliferation and differentiation. |
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