Boldine Attenuates Synaptic Failure and Mitochondrial Deregulation in Cellular Models of Alzheimer's Disease

Detalhes bibliográficos
Autor(a) principal: Toledo, Juan P.
Data de Publicação: 2021
Outros Autores: Fernández-Pérez, Eduardo J., Ferreira, Ildete L., Marinho, Daniela, Riffo-Lepe, Nicolas O., Pineda-Cuevas, Benjamin N., Pinochet-Pino, Luis F., Burgos, Carlos F., Rego, A. Cristina, Aguayo, Luis G.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10316/104543
https://doi.org/10.3389/fnins.2021.617821
Resumo: Alzheimer's disease (AD) is the most common cause of senile dementia worldwide, characterized by both cognitive and behavioral deficits. Amyloid beta peptide (Aβ) oligomers (AβO) have been found to be responsible for several pathological mechanisms during the development of AD, including altered cellular homeostasis and synaptic function, inevitably leading to cell death. Such AβO deleterious effects provide a way for identifying new molecules with potential anti-AD properties. Available treatments minimally improve AD symptoms and do not extensively target intracellular pathways affected by AβO. Naturally-derived compounds have been proposed as potential modifiers of Aβ-induced neurodysfunction and cytotoxicity based on their availability and chemical diversity. Thus, the aim of this study was to evaluate boldine, an alkaloid derived from the bark and leaves of the Chilean tree Peumus boldus, and its capacity to block some dysfunctional processes caused by AβO. We examined the protective effect of boldine (1-10 μM) in primary hippocampal neurons and HT22 hippocampal-derived cell line treated with AβO (24-48 h). We found that boldine interacts with Aβ in silico affecting its aggregation and protecting hippocampal neurons from synaptic failure induced by AβO. Boldine also normalized changes in intracellular Ca2+ levels associated to mitochondria or endoplasmic reticulum in HT22 cells treated with AβO. In addition, boldine completely rescued the decrease in mitochondrial membrane potential (ΔΨm) and the increase in mitochondrial reactive oxygen species, and attenuated AβO-induced decrease in mitochondrial respiration in HT22 hippocampal cells. We conclude that boldine provides neuroprotection in AD models by both direct interactions with Aβ and by preventing oxidative stress and mitochondrial dysfunction. Additional studies are required to evaluate the effect of boldine on cognitive and behavioral deficits induced by Aβ in vivo.
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spelling Boldine Attenuates Synaptic Failure and Mitochondrial Deregulation in Cellular Models of Alzheimer's DiseaseAlzheimer’s diseaseBoldinemitochondriasynaptic transmissionintracellular Ca2CAlzheimer's disease (AD) is the most common cause of senile dementia worldwide, characterized by both cognitive and behavioral deficits. Amyloid beta peptide (Aβ) oligomers (AβO) have been found to be responsible for several pathological mechanisms during the development of AD, including altered cellular homeostasis and synaptic function, inevitably leading to cell death. Such AβO deleterious effects provide a way for identifying new molecules with potential anti-AD properties. Available treatments minimally improve AD symptoms and do not extensively target intracellular pathways affected by AβO. Naturally-derived compounds have been proposed as potential modifiers of Aβ-induced neurodysfunction and cytotoxicity based on their availability and chemical diversity. Thus, the aim of this study was to evaluate boldine, an alkaloid derived from the bark and leaves of the Chilean tree Peumus boldus, and its capacity to block some dysfunctional processes caused by AβO. We examined the protective effect of boldine (1-10 μM) in primary hippocampal neurons and HT22 hippocampal-derived cell line treated with AβO (24-48 h). We found that boldine interacts with Aβ in silico affecting its aggregation and protecting hippocampal neurons from synaptic failure induced by AβO. Boldine also normalized changes in intracellular Ca2+ levels associated to mitochondria or endoplasmic reticulum in HT22 cells treated with AβO. In addition, boldine completely rescued the decrease in mitochondrial membrane potential (ΔΨm) and the increase in mitochondrial reactive oxygen species, and attenuated AβO-induced decrease in mitochondrial respiration in HT22 hippocampal cells. We conclude that boldine provides neuroprotection in AD models by both direct interactions with Aβ and by preventing oxidative stress and mitochondrial dysfunction. Additional studies are required to evaluate the effect of boldine on cognitive and behavioral deficits induced by Aβ in vivo.Frontiers Media S.A.2021info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/104543http://hdl.handle.net/10316/104543https://doi.org/10.3389/fnins.2021.617821eng1662-4548Toledo, Juan P.Fernández-Pérez, Eduardo J.Ferreira, Ildete L.Marinho, DanielaRiffo-Lepe, Nicolas O.Pineda-Cuevas, Benjamin N.Pinochet-Pino, Luis F.Burgos, Carlos F.Rego, A. CristinaAguayo, Luis G.info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-01-17T21:47:15Zoai:estudogeral.uc.pt:10316/104543Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:21:14.272089Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Boldine Attenuates Synaptic Failure and Mitochondrial Deregulation in Cellular Models of Alzheimer's Disease
title Boldine Attenuates Synaptic Failure and Mitochondrial Deregulation in Cellular Models of Alzheimer's Disease
spellingShingle Boldine Attenuates Synaptic Failure and Mitochondrial Deregulation in Cellular Models of Alzheimer's Disease
Toledo, Juan P.
Alzheimer’s disease
Boldine
mitochondria
synaptic transmission
intracellular Ca2C
title_short Boldine Attenuates Synaptic Failure and Mitochondrial Deregulation in Cellular Models of Alzheimer's Disease
title_full Boldine Attenuates Synaptic Failure and Mitochondrial Deregulation in Cellular Models of Alzheimer's Disease
title_fullStr Boldine Attenuates Synaptic Failure and Mitochondrial Deregulation in Cellular Models of Alzheimer's Disease
title_full_unstemmed Boldine Attenuates Synaptic Failure and Mitochondrial Deregulation in Cellular Models of Alzheimer's Disease
title_sort Boldine Attenuates Synaptic Failure and Mitochondrial Deregulation in Cellular Models of Alzheimer's Disease
author Toledo, Juan P.
author_facet Toledo, Juan P.
Fernández-Pérez, Eduardo J.
Ferreira, Ildete L.
Marinho, Daniela
Riffo-Lepe, Nicolas O.
Pineda-Cuevas, Benjamin N.
Pinochet-Pino, Luis F.
Burgos, Carlos F.
Rego, A. Cristina
Aguayo, Luis G.
author_role author
author2 Fernández-Pérez, Eduardo J.
Ferreira, Ildete L.
Marinho, Daniela
Riffo-Lepe, Nicolas O.
Pineda-Cuevas, Benjamin N.
Pinochet-Pino, Luis F.
Burgos, Carlos F.
Rego, A. Cristina
Aguayo, Luis G.
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.author.fl_str_mv Toledo, Juan P.
Fernández-Pérez, Eduardo J.
Ferreira, Ildete L.
Marinho, Daniela
Riffo-Lepe, Nicolas O.
Pineda-Cuevas, Benjamin N.
Pinochet-Pino, Luis F.
Burgos, Carlos F.
Rego, A. Cristina
Aguayo, Luis G.
dc.subject.por.fl_str_mv Alzheimer’s disease
Boldine
mitochondria
synaptic transmission
intracellular Ca2C
topic Alzheimer’s disease
Boldine
mitochondria
synaptic transmission
intracellular Ca2C
description Alzheimer's disease (AD) is the most common cause of senile dementia worldwide, characterized by both cognitive and behavioral deficits. Amyloid beta peptide (Aβ) oligomers (AβO) have been found to be responsible for several pathological mechanisms during the development of AD, including altered cellular homeostasis and synaptic function, inevitably leading to cell death. Such AβO deleterious effects provide a way for identifying new molecules with potential anti-AD properties. Available treatments minimally improve AD symptoms and do not extensively target intracellular pathways affected by AβO. Naturally-derived compounds have been proposed as potential modifiers of Aβ-induced neurodysfunction and cytotoxicity based on their availability and chemical diversity. Thus, the aim of this study was to evaluate boldine, an alkaloid derived from the bark and leaves of the Chilean tree Peumus boldus, and its capacity to block some dysfunctional processes caused by AβO. We examined the protective effect of boldine (1-10 μM) in primary hippocampal neurons and HT22 hippocampal-derived cell line treated with AβO (24-48 h). We found that boldine interacts with Aβ in silico affecting its aggregation and protecting hippocampal neurons from synaptic failure induced by AβO. Boldine also normalized changes in intracellular Ca2+ levels associated to mitochondria or endoplasmic reticulum in HT22 cells treated with AβO. In addition, boldine completely rescued the decrease in mitochondrial membrane potential (ΔΨm) and the increase in mitochondrial reactive oxygen species, and attenuated AβO-induced decrease in mitochondrial respiration in HT22 hippocampal cells. We conclude that boldine provides neuroprotection in AD models by both direct interactions with Aβ and by preventing oxidative stress and mitochondrial dysfunction. Additional studies are required to evaluate the effect of boldine on cognitive and behavioral deficits induced by Aβ in vivo.
publishDate 2021
dc.date.none.fl_str_mv 2021
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
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dc.identifier.uri.fl_str_mv http://hdl.handle.net/10316/104543
http://hdl.handle.net/10316/104543
https://doi.org/10.3389/fnins.2021.617821
url http://hdl.handle.net/10316/104543
https://doi.org/10.3389/fnins.2021.617821
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv 1662-4548
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dc.publisher.none.fl_str_mv Frontiers Media S.A.
publisher.none.fl_str_mv Frontiers Media S.A.
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
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