Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer's disease

Autores
Iulita, M. Florencia; Bistue Millon, Maria Beatriz; Pentz, Rowan; Aguilar, Lisi Flores; Do Carmo, Sonia; Allard, Simon; Michalski, Bernadeta; Wilson, Edward N.; Ducatenzeiler, Adriana; Bruno, Martin; Fahnestock, Margaret; Cuello, A. Claudio
Año de publicación
2017
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Evidence from human neuropathological studies indicates that the levels of the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are compromised in Alzheimer's disease. However, the causes and temporal (pathology-dependent) evolution of these alterations are not completely understood. To elucidate these issues, we investigated the McGill-R-Thy1-APP transgenic rat, which exhibits progressive intracellular and extracellular amyloid-beta (Aβ) pathology and ensuing cognitive deficits. Neurochemical analyses revealed a differential dysregulation of NGF and BDNF transcripts and protein expression. While BDNF mRNA levels were significantly reduced at very early stages of amyloid pathology, before plaques appeared, there were no changes in NGF mRNA expression even at advanced stages. Paradoxically, the protein levels of the NGF precursor were increased. These changes in neurotrophin expression are identical to those seen during the progression of Alzheimer's disease. At advanced pathological stages, deficits in the protease cascade controlling the maturation and degradation of NGF were evident in McGill transgenic rats, in line with the paradoxical upregulation of proNGF, as seen in Alzheimer's disease, in the absence of changes in NGF mRNA. The compromise in NGF metabolism and BDNF levels was accompanied by downregulation of cortical cholinergic synapses; strengthening the evidence that neurotrophin dysregulation affects cholinergic synapses and synaptic plasticity. Our findings suggest a differential temporal deregulation of NGF and BDNF neurotrophins, whereby deficits in BDNF mRNA appear at early stages of intraneuronal Aβ pathology, before alterations in NGF metabolism and cholinergic synapse loss manifest.
Fil: Iulita, M. Florencia. McGill University; Canadá
Fil: Bistue Millon, Maria Beatriz. Universidad Católica de Cuyo - Sede San Juan. Facultad de Ciencias Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Pentz, Rowan. Universidad Católica de Cuyo - Sede San Juan. Facultad de Ciencias Médicas; Argentina
Fil: Aguilar, Lisi Flores. McGill University; Canadá
Fil: Do Carmo, Sonia. McGill University; Canadá
Fil: Allard, Simon. McGill University; Canadá
Fil: Michalski, Bernadeta. Mc Master University; Canadá
Fil: Wilson, Edward N.. McGill University; Canadá
Fil: Ducatenzeiler, Adriana. Universidad Católica de Cuyo - Sede San Juan. Facultad de Ciencias Médicas; Argentina
Fil: Bruno, Martin. Universidad Católica de Cuyo - Sede San Juan. Facultad de Ciencias Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Fahnestock, Margaret. Mc Master University; Canadá
Fil: Cuello, A. Claudio. McGill University; Canadá
Materia
Alzheimer'S Disease
Amyloid-Β
Bdnf
Cholinergic
Mmp-9
Nerve Growth Factor
Neuroserpin
Neurotrophins
Prongf
Synaptic Plasticity
Tpa
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/69227
Acceder
id CONICETDig_0c8cb6e5dfc1e2d1f9a607e2d6268eed
oai_identifier_str oai:ri.conicet.gov.ar:11336/69227
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer's diseaseIulita, M. FlorenciaBistue Millon, Maria BeatrizPentz, RowanAguilar, Lisi FloresDo Carmo, SoniaAllard, SimonMichalski, BernadetaWilson, Edward N.Ducatenzeiler, AdrianaBruno, MartinFahnestock, MargaretCuello, A. ClaudioAlzheimer'S DiseaseAmyloid-ΒBdnfCholinergicMmp-9Nerve Growth FactorNeuroserpinNeurotrophinsProngfSynaptic PlasticityTpahttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Evidence from human neuropathological studies indicates that the levels of the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are compromised in Alzheimer's disease. However, the causes and temporal (pathology-dependent) evolution of these alterations are not completely understood. To elucidate these issues, we investigated the McGill-R-Thy1-APP transgenic rat, which exhibits progressive intracellular and extracellular amyloid-beta (Aβ) pathology and ensuing cognitive deficits. Neurochemical analyses revealed a differential dysregulation of NGF and BDNF transcripts and protein expression. While BDNF mRNA levels were significantly reduced at very early stages of amyloid pathology, before plaques appeared, there were no changes in NGF mRNA expression even at advanced stages. Paradoxically, the protein levels of the NGF precursor were increased. These changes in neurotrophin expression are identical to those seen during the progression of Alzheimer's disease. At advanced pathological stages, deficits in the protease cascade controlling the maturation and degradation of NGF were evident in McGill transgenic rats, in line with the paradoxical upregulation of proNGF, as seen in Alzheimer's disease, in the absence of changes in NGF mRNA. The compromise in NGF metabolism and BDNF levels was accompanied by downregulation of cortical cholinergic synapses; strengthening the evidence that neurotrophin dysregulation affects cholinergic synapses and synaptic plasticity. Our findings suggest a differential temporal deregulation of NGF and BDNF neurotrophins, whereby deficits in BDNF mRNA appear at early stages of intraneuronal Aβ pathology, before alterations in NGF metabolism and cholinergic synapse loss manifest.Fil: Iulita, M. Florencia. McGill University; CanadáFil: Bistue Millon, Maria Beatriz. Universidad Católica de Cuyo - Sede San Juan. Facultad de Ciencias Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Pentz, Rowan. Universidad Católica de Cuyo - Sede San Juan. Facultad de Ciencias Médicas; ArgentinaFil: Aguilar, Lisi Flores. McGill University; CanadáFil: Do Carmo, Sonia. McGill University; CanadáFil: Allard, Simon. McGill University; CanadáFil: Michalski, Bernadeta. Mc Master University; CanadáFil: Wilson, Edward N.. McGill University; CanadáFil: Ducatenzeiler, Adriana. Universidad Católica de Cuyo - Sede San Juan. Facultad de Ciencias Médicas; ArgentinaFil: Bruno, Martin. Universidad Católica de Cuyo - Sede San Juan. Facultad de Ciencias Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fahnestock, Margaret. Mc Master University; CanadáFil: Cuello, A. Claudio. McGill University; CanadáAcademic Press Inc Elsevier Science2017-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/69227Iulita, M. Florencia; Bistue Millon, Maria Beatriz; Pentz, Rowan; Aguilar, Lisi Flores; Do Carmo, Sonia; et al.; Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer's disease; Academic Press Inc Elsevier Science; Neurobiology of Disease; 108; 12-2017; 307-3230969-9961CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.nbd.2017.08.019info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0969996117302097info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:50:39Zoai:ri.conicet.gov.ar:11336/69227instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:50:40.199CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer's disease
title Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer's disease
spellingShingle Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer's disease
Iulita, M. Florencia
Alzheimer'S Disease
Amyloid-Β
Bdnf
Cholinergic
Mmp-9
Nerve Growth Factor
Neuroserpin
Neurotrophins
Prongf
Synaptic Plasticity
Tpa
title_short Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer's disease
title_full Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer's disease
title_fullStr Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer's disease
title_full_unstemmed Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer's disease
title_sort Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer's disease
dc.creator.none.fl_str_mv Iulita, M. Florencia
Bistue Millon, Maria Beatriz
Pentz, Rowan
Aguilar, Lisi Flores
Do Carmo, Sonia
Allard, Simon
Michalski, Bernadeta
Wilson, Edward N.
Ducatenzeiler, Adriana
Bruno, Martin
Fahnestock, Margaret
Cuello, A. Claudio
author Iulita, M. Florencia
author_facet Iulita, M. Florencia
Bistue Millon, Maria Beatriz
Pentz, Rowan
Aguilar, Lisi Flores
Do Carmo, Sonia
Allard, Simon
Michalski, Bernadeta
Wilson, Edward N.
Ducatenzeiler, Adriana
Bruno, Martin
Fahnestock, Margaret
Cuello, A. Claudio
author_role author
author2 Bistue Millon, Maria Beatriz
Pentz, Rowan
Aguilar, Lisi Flores
Do Carmo, Sonia
Allard, Simon
Michalski, Bernadeta
Wilson, Edward N.
Ducatenzeiler, Adriana
Bruno, Martin
Fahnestock, Margaret
Cuello, A. Claudio
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Alzheimer'S Disease
Amyloid-Β
Bdnf
Cholinergic
Mmp-9
Nerve Growth Factor
Neuroserpin
Neurotrophins
Prongf
Synaptic Plasticity
Tpa
topic Alzheimer'S Disease
Amyloid-Β
Bdnf
Cholinergic
Mmp-9
Nerve Growth Factor
Neuroserpin
Neurotrophins
Prongf
Synaptic Plasticity
Tpa
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Evidence from human neuropathological studies indicates that the levels of the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are compromised in Alzheimer's disease. However, the causes and temporal (pathology-dependent) evolution of these alterations are not completely understood. To elucidate these issues, we investigated the McGill-R-Thy1-APP transgenic rat, which exhibits progressive intracellular and extracellular amyloid-beta (Aβ) pathology and ensuing cognitive deficits. Neurochemical analyses revealed a differential dysregulation of NGF and BDNF transcripts and protein expression. While BDNF mRNA levels were significantly reduced at very early stages of amyloid pathology, before plaques appeared, there were no changes in NGF mRNA expression even at advanced stages. Paradoxically, the protein levels of the NGF precursor were increased. These changes in neurotrophin expression are identical to those seen during the progression of Alzheimer's disease. At advanced pathological stages, deficits in the protease cascade controlling the maturation and degradation of NGF were evident in McGill transgenic rats, in line with the paradoxical upregulation of proNGF, as seen in Alzheimer's disease, in the absence of changes in NGF mRNA. The compromise in NGF metabolism and BDNF levels was accompanied by downregulation of cortical cholinergic synapses; strengthening the evidence that neurotrophin dysregulation affects cholinergic synapses and synaptic plasticity. Our findings suggest a differential temporal deregulation of NGF and BDNF neurotrophins, whereby deficits in BDNF mRNA appear at early stages of intraneuronal Aβ pathology, before alterations in NGF metabolism and cholinergic synapse loss manifest.
Fil: Iulita, M. Florencia. McGill University; Canadá
Fil: Bistue Millon, Maria Beatriz. Universidad Católica de Cuyo - Sede San Juan. Facultad de Ciencias Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Pentz, Rowan. Universidad Católica de Cuyo - Sede San Juan. Facultad de Ciencias Médicas; Argentina
Fil: Aguilar, Lisi Flores. McGill University; Canadá
Fil: Do Carmo, Sonia. McGill University; Canadá
Fil: Allard, Simon. McGill University; Canadá
Fil: Michalski, Bernadeta. Mc Master University; Canadá
Fil: Wilson, Edward N.. McGill University; Canadá
Fil: Ducatenzeiler, Adriana. Universidad Católica de Cuyo - Sede San Juan. Facultad de Ciencias Médicas; Argentina
Fil: Bruno, Martin. Universidad Católica de Cuyo - Sede San Juan. Facultad de Ciencias Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Fahnestock, Margaret. Mc Master University; Canadá
Fil: Cuello, A. Claudio. McGill University; Canadá
description Evidence from human neuropathological studies indicates that the levels of the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are compromised in Alzheimer's disease. However, the causes and temporal (pathology-dependent) evolution of these alterations are not completely understood. To elucidate these issues, we investigated the McGill-R-Thy1-APP transgenic rat, which exhibits progressive intracellular and extracellular amyloid-beta (Aβ) pathology and ensuing cognitive deficits. Neurochemical analyses revealed a differential dysregulation of NGF and BDNF transcripts and protein expression. While BDNF mRNA levels were significantly reduced at very early stages of amyloid pathology, before plaques appeared, there were no changes in NGF mRNA expression even at advanced stages. Paradoxically, the protein levels of the NGF precursor were increased. These changes in neurotrophin expression are identical to those seen during the progression of Alzheimer's disease. At advanced pathological stages, deficits in the protease cascade controlling the maturation and degradation of NGF were evident in McGill transgenic rats, in line with the paradoxical upregulation of proNGF, as seen in Alzheimer's disease, in the absence of changes in NGF mRNA. The compromise in NGF metabolism and BDNF levels was accompanied by downregulation of cortical cholinergic synapses; strengthening the evidence that neurotrophin dysregulation affects cholinergic synapses and synaptic plasticity. Our findings suggest a differential temporal deregulation of NGF and BDNF neurotrophins, whereby deficits in BDNF mRNA appear at early stages of intraneuronal Aβ pathology, before alterations in NGF metabolism and cholinergic synapse loss manifest.
publishDate 2017
dc.date.none.fl_str_mv 2017-12
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/69227
Iulita, M. Florencia; Bistue Millon, Maria Beatriz; Pentz, Rowan; Aguilar, Lisi Flores; Do Carmo, Sonia; et al.; Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer's disease; Academic Press Inc Elsevier Science; Neurobiology of Disease; 108; 12-2017; 307-323
0969-9961
CONICET Digital
CONICET
url http://hdl.handle.net/11336/69227
identifier_str_mv Iulita, M. Florencia; Bistue Millon, Maria Beatriz; Pentz, Rowan; Aguilar, Lisi Flores; Do Carmo, Sonia; et al.; Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer's disease; Academic Press Inc Elsevier Science; Neurobiology of Disease; 108; 12-2017; 307-323
0969-9961
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.nbd.2017.08.019
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0969996117302097
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Academic Press Inc Elsevier Science
publisher.none.fl_str_mv Academic Press Inc Elsevier Science
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.13397

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