Tauopathy analysis in P301S mouse model of alzheimer disease immunized with DNA and MVA poxvirus-based vaccines expressing human full-length 4R2N or 3RC Tau proteins
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a progressive memory loss and cognitive decline that has been associated with an accumulation in the brain of intracellular neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau protein, and extracellular senile pla...
| Autores: | , , , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2020 |
| País: | España |
| Institución: | Universidad Autónoma de Madrid |
| Repositorio: | Biblos-e Archivo. Repositorio Institucional de la UAM |
| Idioma: | inglés |
| OAI Identifier: | oai:repositorio.uam.es:10486/717588 |
| Acceso en línea: | http://hdl.handle.net/10486/717588 https://dx.doi.org/10.3390/vaccines8010127 |
| Access Level: | acceso abierto |
| Palabra clave: | Alzheimer MVA P301S transgenic mice pathology poxvirus tau Biología y Biomedicina / Biología |
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oai:repositorio.uam.es:10486/717588 |
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Tauopathy analysis in P301S mouse model of alzheimer disease immunized with DNA and MVA poxvirus-based vaccines expressing human full-length 4R2N or 3RC Tau proteins García Arriaza, Juan Francisco Marín, María Q. Merchán-Rubira, Jesús Mascaraque, Sara M. Medina, Miguel Ávila, Jesús Esteban, Mariano Hernández Pérez, Félix Alzheimer MVA P301S transgenic mice pathology poxvirus tau Biología y Biomedicina / Biología Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a progressive memory loss and cognitive decline that has been associated with an accumulation in the brain of intracellular neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau protein, and extracellular senile plaques formed by β-amyloid peptides. Currently, there is no cure for AD and after the failure of anti β-amyloid therapies, active and passive tau immunotherapeutic approaches have been developed in order to prevent, reduce or ideally reverse the disease. Vaccination is one of the most effective approaches to prevent diseases and poxviruses, particularly modified vaccinia virus Ankara (MVA), are one of the most promising viral vectors used as vaccines against several human diseases. Thus, we present here the generation and characterization of the first MVA vectors expressing human tau genes; the full-length 4R2N tau protein or a 3RC tau fragment containing 3 tubulin-binding motifs and the C- terminal region (termed MVA-Tau4R2N and MVA-Tau3RC, respectively). Both MVA-Tau recombinant viruses efficiently expressed the human tau 4R2N or 3RC proteins in cultured cells, being detected in the cytoplasm of infected cells and co-localized with tubulin. These MVA-Tau vaccines impacted the innate immune responses with a differential recruitment of innate immune cells to the peritoneal cavity of infected mice. However, no tau-specific T cell or humoral immune responses were detected in vaccinated mice. Immunization of transgenic P301S mice, a mouse model for tauopathies, with a DNA-Tau prime/MVA-Tau boost approach showed no significant differences in the hyperphosphorylation of tau, motor capacity and survival rate, when compared to non-vaccinated mice. These findings showed that a well-established and potent protocol of T and B cell activation based on DNA/MVA prime/boost regimens using DNA and MVA vectors expressing tau full-length 4R2N or 3RC proteins is not sufficient to trigger tau-specific T and B cell immune responses and to induce a protective effect against tauopathy in this P301S murine model. In the pursuit of AD vaccines, our results highlight the need for novel optimized tau immunogens and additional modes of presentation of tau protein to the immune system Acknowledgments: María Q. Marín received a Formación del Profesorado Universitario PhD fellowship, from the Spanish Ministry of Education and a short‐term EMBO fellowship; Jesús Merchán‐Rubira received a PhD fellowship from Fundación “La Caixa”. We thank Cristina Sánchez Corzo and Victoria Jiménez for expert technical assistance in cell culture, virus growth and purification, and Silvia Gutiérrez and Ana Oña from the CNB Advanced Light Microscopy Facility for their valuable support in confocal microscopy experiments. MDPI http://hdl.handle.net/10486/717588 https://dx.doi.org/10.3390/vaccines8010127 |
| title |
Tauopathy analysis in P301S mouse model of alzheimer disease immunized with DNA and MVA poxvirus-based vaccines expressing human full-length 4R2N or 3RC Tau proteins |
| spellingShingle |
Tauopathy analysis in P301S mouse model of alzheimer disease immunized with DNA and MVA poxvirus-based vaccines expressing human full-length 4R2N or 3RC Tau proteins García Arriaza, Juan Francisco Alzheimer MVA P301S transgenic mice pathology poxvirus tau Biología y Biomedicina / Biología |
| title_short |
Tauopathy analysis in P301S mouse model of alzheimer disease immunized with DNA and MVA poxvirus-based vaccines expressing human full-length 4R2N or 3RC Tau proteins |
| title_full |
Tauopathy analysis in P301S mouse model of alzheimer disease immunized with DNA and MVA poxvirus-based vaccines expressing human full-length 4R2N or 3RC Tau proteins |
| title_fullStr |
Tauopathy analysis in P301S mouse model of alzheimer disease immunized with DNA and MVA poxvirus-based vaccines expressing human full-length 4R2N or 3RC Tau proteins |
| title_full_unstemmed |
Tauopathy analysis in P301S mouse model of alzheimer disease immunized with DNA and MVA poxvirus-based vaccines expressing human full-length 4R2N or 3RC Tau proteins |
| title_sort |
Tauopathy analysis in P301S mouse model of alzheimer disease immunized with DNA and MVA poxvirus-based vaccines expressing human full-length 4R2N or 3RC Tau proteins |
| author |
García Arriaza, Juan Francisco |
| author_facet |
García Arriaza, Juan Francisco Marín, María Q. Merchán-Rubira, Jesús Mascaraque, Sara M. Medina, Miguel Ávila, Jesús Esteban, Mariano Hernández Pérez, Félix |
| author_role |
author |
| author2 |
Marín, María Q. Merchán-Rubira, Jesús Mascaraque, Sara M. Medina, Miguel Ávila, Jesús Esteban, Mariano Hernández Pérez, Félix |
| author2_role |
author author author author author author author |
| topic |
Alzheimer MVA P301S transgenic mice pathology poxvirus tau Biología y Biomedicina / Biología |
| topic_facet |
Alzheimer MVA P301S transgenic mice pathology poxvirus tau Biología y Biomedicina / Biología |
| description |
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a progressive memory loss and cognitive decline that has been associated with an accumulation in the brain of intracellular neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau protein, and extracellular senile plaques formed by β-amyloid peptides. Currently, there is no cure for AD and after the failure of anti β-amyloid therapies, active and passive tau immunotherapeutic approaches have been developed in order to prevent, reduce or ideally reverse the disease. Vaccination is one of the most effective approaches to prevent diseases and poxviruses, particularly modified vaccinia virus Ankara (MVA), are one of the most promising viral vectors used as vaccines against several human diseases. Thus, we present here the generation and characterization of the first MVA vectors expressing human tau genes; the full-length 4R2N tau protein or a 3RC tau fragment containing 3 tubulin-binding motifs and the C- terminal region (termed MVA-Tau4R2N and MVA-Tau3RC, respectively). Both MVA-Tau recombinant viruses efficiently expressed the human tau 4R2N or 3RC proteins in cultured cells, being detected in the cytoplasm of infected cells and co-localized with tubulin. These MVA-Tau vaccines impacted the innate immune responses with a differential recruitment of innate immune cells to the peritoneal cavity of infected mice. However, no tau-specific T cell or humoral immune responses were detected in vaccinated mice. Immunization of transgenic P301S mice, a mouse model for tauopathies, with a DNA-Tau prime/MVA-Tau boost approach showed no significant differences in the hyperphosphorylation of tau, motor capacity and survival rate, when compared to non-vaccinated mice. These findings showed that a well-established and potent protocol of T and B cell activation based on DNA/MVA prime/boost regimens using DNA and MVA vectors expressing tau full-length 4R2N or 3RC proteins is not sufficient to trigger tau-specific T and B cell immune responses and to induce a protective effect against tauopathy in this P301S murine model. In the pursuit of AD vaccines, our results highlight the need for novel optimized tau immunogens and additional modes of presentation of tau protein to the immune system |
| publishDate |
2020 |
| format |
article |
| url |
http://hdl.handle.net/10486/717588 https://dx.doi.org/10.3390/vaccines8010127 |
| language |
eng |
| eu_rights_str_mv |
openAccess |
| publisher |
MDPI |
| institution |
Universidad Autónoma de Madrid |
| collection |
Biblos-e Archivo. Repositorio Institucional de la UAM |
| reponame_str |
Biblos-e Archivo. Repositorio Institucional de la UAM |
| instname_str |
Universidad Autónoma de Madrid |
| _version_ |
1878443448755814400 |
| publishDateSort |
2020 |
| author_browse |
Esteban, Mariano García Arriaza, Juan Francisco Hernández Pérez, Félix Marín, María Q. Mascaraque, Sara M. Medina, Miguel Merchán-Rubira, Jesús Ávila, Jesús |
| publisherStr |
MDPI |
| score |
6,924472 |