miRNA-31 Improves Cognition and Abolishes Amyloid-β Pathology by Targeting APP and BACE1 in an Animal Model of Alzheimer's Disease

Detalhes bibliográficos
Autor(a) principal: Barros-Viegas, Ana Teresa
Data de Publicação: 2020
Outros Autores: Carmona, Vitor, Ferreiro, Elisabete, Guedes, Joana, Cardoso, Ana Maria S., Cunha, Pedro, Almeida, Luís Pereira de, Oliveira, Catarina Resende de, Magalhães, João Pedro de, Peça, João, Cardoso, Ana Luísa
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10316/106459
https://doi.org/10.1016/j.omtn.2020.01.010
Resumo: Alzheimer's disease (AD) is the most common form of dementia worldwide, characterized by progressive memory impairment, behavioral changes, and, ultimately, loss of consciousness and death. Recently, microRNA (miRNA) dysfunction has been associated with increased production and impaired clearance of amyloid-β (Aβ) peptides, whose accumulation is one of the most well-known pathophysiological markers of this disease. In this study, we identified several miRNAs capable of targeting key proteins of the amyloidogenic pathway. The expression of one of these miRNAs, miR-31, previously found to be decreased in AD patients, was able to simultaneously reduce the levels of APP and Bace1 mRNA in the hippocampus of 17-month-old AD triple-transgenic (3xTg-AD) female mice, leading to a significant improvement of memory deficits and a reduction in anxiety and cognitive inflexibility. In addition, lentiviral-mediated miR-31 expression significantly ameliorated AD neuropathology in this model, drastically reducing Aβ deposition in both the hippocampus and subiculum. Furthermore, the increase of miR-31 levels was enough to reduce the accumulation of glutamate vesicles in the hippocampus to levels found in non-transgenic age-matched animals. Overall, our results suggest that miR-31-mediated modulation of APP and BACE1 can become a therapeutic option in the treatment of AD.
id RCAP_76fe7b321c11f9ae1a4c19d1a4437624
oai_identifier_str oai:estudogeral.uc.pt:10316/106459
network_acronym_str RCAP
network_name_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository_id_str 7160
spelling miRNA-31 Improves Cognition and Abolishes Amyloid-β Pathology by Targeting APP and BACE1 in an Animal Model of Alzheimer's DiseaseAlzheimer’s diseasemiR-31gene therapylentiviral vectorAPPBACE1amyloid-β peptidecognitive functionmemoryAlzheimer's disease (AD) is the most common form of dementia worldwide, characterized by progressive memory impairment, behavioral changes, and, ultimately, loss of consciousness and death. Recently, microRNA (miRNA) dysfunction has been associated with increased production and impaired clearance of amyloid-β (Aβ) peptides, whose accumulation is one of the most well-known pathophysiological markers of this disease. In this study, we identified several miRNAs capable of targeting key proteins of the amyloidogenic pathway. The expression of one of these miRNAs, miR-31, previously found to be decreased in AD patients, was able to simultaneously reduce the levels of APP and Bace1 mRNA in the hippocampus of 17-month-old AD triple-transgenic (3xTg-AD) female mice, leading to a significant improvement of memory deficits and a reduction in anxiety and cognitive inflexibility. In addition, lentiviral-mediated miR-31 expression significantly ameliorated AD neuropathology in this model, drastically reducing Aβ deposition in both the hippocampus and subiculum. Furthermore, the increase of miR-31 levels was enough to reduce the accumulation of glutamate vesicles in the hippocampus to levels found in non-transgenic age-matched animals. Overall, our results suggest that miR-31-mediated modulation of APP and BACE1 can become a therapeutic option in the treatment of AD.This work was financed by the European Regional Development Fund (ERDF), through the Centro 2020 Regional Operational Programme under the project CENTRO-01-0145-FEDER-000008: BrainHealth 2020 and through the COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation and Portuguese national funds via FCT - Fundação para a Ciência e a Tecnologia, under the project POCI- 01-0145-FEDER-007440 (reference UID/NEU/04539/2013). This work was also supported by the FCT Investigator Programme (IF/ 00694/2013 to J.P.), the Marie Curie Carrier Integration Grant (PCIG13-GA-2013-618525 to J.P.), HEALTHYAGING 2020 (CENTRO-01-0145-FEDER-000012 to A.T.B.-V.), and Bial Foundation Grant 264/16. A.T.B.-V., J.G., and A.L.C. are recipients of fellowships from the FCT (Grants PTDC/BIM-MEC/0651/2012, SFRH/ BPD/120611/2016, and SFRH/BPD/108312/2015).Elsevier2020-03-06info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/106459http://hdl.handle.net/10316/106459https://doi.org/10.1016/j.omtn.2020.01.010eng2162-2531Barros-Viegas, Ana TeresaCarmona, VitorFerreiro, ElisabeteGuedes, JoanaCardoso, Ana Maria S.Cunha, PedroAlmeida, Luís Pereira deOliveira, Catarina Resende deMagalhães, João Pedro dePeça, JoãoCardoso, Ana Luísainfo: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:RCAAP2023-04-06T10:19:58Zoai:estudogeral.uc.pt:10316/106459Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:22:54.614315Repositório 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 miRNA-31 Improves Cognition and Abolishes Amyloid-β Pathology by Targeting APP and BACE1 in an Animal Model of Alzheimer's Disease
title miRNA-31 Improves Cognition and Abolishes Amyloid-β Pathology by Targeting APP and BACE1 in an Animal Model of Alzheimer's Disease
spellingShingle miRNA-31 Improves Cognition and Abolishes Amyloid-β Pathology by Targeting APP and BACE1 in an Animal Model of Alzheimer's Disease
Barros-Viegas, Ana Teresa
Alzheimer’s disease
miR-31
gene therapy
lentiviral vector
APP
BACE1
amyloid-β peptide
cognitive function
memory
title_short miRNA-31 Improves Cognition and Abolishes Amyloid-β Pathology by Targeting APP and BACE1 in an Animal Model of Alzheimer's Disease
title_full miRNA-31 Improves Cognition and Abolishes Amyloid-β Pathology by Targeting APP and BACE1 in an Animal Model of Alzheimer's Disease
title_fullStr miRNA-31 Improves Cognition and Abolishes Amyloid-β Pathology by Targeting APP and BACE1 in an Animal Model of Alzheimer's Disease
title_full_unstemmed miRNA-31 Improves Cognition and Abolishes Amyloid-β Pathology by Targeting APP and BACE1 in an Animal Model of Alzheimer's Disease
title_sort miRNA-31 Improves Cognition and Abolishes Amyloid-β Pathology by Targeting APP and BACE1 in an Animal Model of Alzheimer's Disease
author Barros-Viegas, Ana Teresa
author_facet Barros-Viegas, Ana Teresa
Carmona, Vitor
Ferreiro, Elisabete
Guedes, Joana
Cardoso, Ana Maria S.
Cunha, Pedro
Almeida, Luís Pereira de
Oliveira, Catarina Resende de
Magalhães, João Pedro de
Peça, João
Cardoso, Ana Luísa
author_role author
author2 Carmona, Vitor
Ferreiro, Elisabete
Guedes, Joana
Cardoso, Ana Maria S.
Cunha, Pedro
Almeida, Luís Pereira de
Oliveira, Catarina Resende de
Magalhães, João Pedro de
Peça, João
Cardoso, Ana Luísa
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.author.fl_str_mv Barros-Viegas, Ana Teresa
Carmona, Vitor
Ferreiro, Elisabete
Guedes, Joana
Cardoso, Ana Maria S.
Cunha, Pedro
Almeida, Luís Pereira de
Oliveira, Catarina Resende de
Magalhães, João Pedro de
Peça, João
Cardoso, Ana Luísa
dc.subject.por.fl_str_mv Alzheimer’s disease
miR-31
gene therapy
lentiviral vector
APP
BACE1
amyloid-β peptide
cognitive function
memory
topic Alzheimer’s disease
miR-31
gene therapy
lentiviral vector
APP
BACE1
amyloid-β peptide
cognitive function
memory
description Alzheimer's disease (AD) is the most common form of dementia worldwide, characterized by progressive memory impairment, behavioral changes, and, ultimately, loss of consciousness and death. Recently, microRNA (miRNA) dysfunction has been associated with increased production and impaired clearance of amyloid-β (Aβ) peptides, whose accumulation is one of the most well-known pathophysiological markers of this disease. In this study, we identified several miRNAs capable of targeting key proteins of the amyloidogenic pathway. The expression of one of these miRNAs, miR-31, previously found to be decreased in AD patients, was able to simultaneously reduce the levels of APP and Bace1 mRNA in the hippocampus of 17-month-old AD triple-transgenic (3xTg-AD) female mice, leading to a significant improvement of memory deficits and a reduction in anxiety and cognitive inflexibility. In addition, lentiviral-mediated miR-31 expression significantly ameliorated AD neuropathology in this model, drastically reducing Aβ deposition in both the hippocampus and subiculum. Furthermore, the increase of miR-31 levels was enough to reduce the accumulation of glutamate vesicles in the hippocampus to levels found in non-transgenic age-matched animals. Overall, our results suggest that miR-31-mediated modulation of APP and BACE1 can become a therapeutic option in the treatment of AD.
publishDate 2020
dc.date.none.fl_str_mv 2020-03-06
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10316/106459
http://hdl.handle.net/10316/106459
https://doi.org/10.1016/j.omtn.2020.01.010
url http://hdl.handle.net/10316/106459
https://doi.org/10.1016/j.omtn.2020.01.010
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv 2162-2531
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
repository.mail.fl_str_mv
_version_ 1799134117268291584