proNGF Involvement in the Adult Neurogenesis Dysfunction in Alzheimer’s Disease

In recent decades, neurogenesis in the adult brain has been well demonstrated in anumber of animal species, including humans. Interestingly, work with rodents has shown that adultneurogenesis in the dentate gyrus (DG) of the hippocampus is vital for some cognitive aspects, asincreasing neurogenesis...

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Autores: Olabiyi, Bolanle Fatimat, Fleitas Pérez, Catherine, Zammou, Bahira, Ferrer, Isidre, Rampon, Claire, Egea Navarro, Joaquim, Espinet Mestre, Carme
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Universitat de Lleida (UdL)
Repositorio:Repositori Obert UdL
OAI Identifier:oai:repositori.udl.cat:10459.1/83631
Acceso en línea:https://doi.org/10.3390/ijms221910744
http://hdl.handle.net/10459.1/83631
Access Level:acceso abierto
Palabra clave:Alzheimer’s disease
Adult neurogenesis
pro-NGF
p75
Dentate gyrus
Memory impairment
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spelling proNGF Involvement in the Adult Neurogenesis Dysfunction in Alzheimer’s DiseaseOlabiyi, Bolanle FatimatFleitas Pérez, CatherineZammou, BahiraFerrer, IsidreRampon, ClaireEgea Navarro, JoaquimEspinet Mestre, CarmeAlzheimer’s diseaseAdult neurogenesispro-NGFp75Dentate gyrusMemory impairmentIn recent decades, neurogenesis in the adult brain has been well demonstrated in anumber of animal species, including humans. Interestingly, work with rodents has shown that adultneurogenesis in the dentate gyrus (DG) of the hippocampus is vital for some cognitive aspects, asincreasing neurogenesis improves memory, while its disruption triggers the opposite effect. Adultneurogenesis declines with age and has been suggested to play a role in impaired progressive learningand memory loss seen in Alzheimer’s disease (AD). Therefore, therapeutic strategies designed toboost adult hippocampal neurogenesis may be beneficial for the treatment of AD. The precursor formsof neurotrophins, such as pro-NGF, display remarkable increase during AD in the hippocampusand entorhinal cortex. In contrast to mature NGF, pro-NGF exerts adverse functions in survival,proliferation, and differentiation. Hence, we hypothesized that pro-NGF and its p75 neurotrophinreceptor (p75NTR) contribute to disrupting adult hippocampal neurogenesis during AD. To test thishypothesis, in this study, we took advantage of the availability of mouse models of AD (APP/PS1),which display memory impairment, and AD human samples to address the role of pro-NGF/p75NTRsignaling in different aspects of adult neurogenesis. First, we observed that DG doublecortin (DCX) +progenitors express p75NTR both, in healthy humans and control animals, although the percentageof DCX+ cells are significantly reduced in AD. Interestingly, the expression of p75NTR in theseprogenitors is significantly decreased in AD conditions compared to controls. In order to assessthe contribution of the pro-NGF/p75NTR pathway to the memory deficits of APP/PS1 mice, weinjected pro-NGF neutralizing antibodies (anti-proNGF) into the DG of control and APP/PS1 miceand animals are subjected to a Morris water maze test. Intriguingly, we observed that anti-pro-NGF significantly restored memory performance of APP/PS1 animals and significantly increasethe percentage of DCX+ progenitors in the DG region of these animals. In summary, our resultssuggest that pro-NGF is involved in disrupting spatial memory in AD, at least in part by blockingadult neurogenesis. Moreover, we propose that adult neurogenesis alteration should be taken intoconsideration for better understanding of AD pathology. Additionally, we provide a new molecularentry point (pro-NGF/p75NTR signaling) as a promising therapeutic target in AD.This work was supported by “Fundació La Marató 2015” (C.E.). We thank, IRB Lleida Biobank (B.0000682), PLATAFORMA BIOBANCOS PT13/0010/0014, HUB-ICO-IDIBELL Biobankfor providing human tissue, and UAI IRBLleida for management supportMDPI2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://doi.org/10.3390/ijms221910744http://hdl.handle.net/10459.1/83631reponame:Repositori Obert UdL instname:Universitat de Lleida (UdL)InglésReproducció del document publicat a: https://doi.org/10.3390/ijms221910744 International Journal of Molecular Sciences, 2021, vol. 22, núm. 19cc-by (c) Authors, 2021info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/4.0/oai:repositori.udl.cat:10459.1/836312026-06-24T12:42:17Z
dc.title.none.fl_str_mv proNGF Involvement in the Adult Neurogenesis Dysfunction in Alzheimer’s Disease
title proNGF Involvement in the Adult Neurogenesis Dysfunction in Alzheimer’s Disease
spellingShingle proNGF Involvement in the Adult Neurogenesis Dysfunction in Alzheimer’s Disease
Olabiyi, Bolanle Fatimat
Alzheimer’s disease
Adult neurogenesis
pro-NGF
p75
Dentate gyrus
Memory impairment
title_short proNGF Involvement in the Adult Neurogenesis Dysfunction in Alzheimer’s Disease
title_full proNGF Involvement in the Adult Neurogenesis Dysfunction in Alzheimer’s Disease
title_fullStr proNGF Involvement in the Adult Neurogenesis Dysfunction in Alzheimer’s Disease
title_full_unstemmed proNGF Involvement in the Adult Neurogenesis Dysfunction in Alzheimer’s Disease
title_sort proNGF Involvement in the Adult Neurogenesis Dysfunction in Alzheimer’s Disease
dc.creator.none.fl_str_mv Olabiyi, Bolanle Fatimat
Fleitas Pérez, Catherine
Zammou, Bahira
Ferrer, Isidre
Rampon, Claire
Egea Navarro, Joaquim
Espinet Mestre, Carme
author Olabiyi, Bolanle Fatimat
author_facet Olabiyi, Bolanle Fatimat
Fleitas Pérez, Catherine
Zammou, Bahira
Ferrer, Isidre
Rampon, Claire
Egea Navarro, Joaquim
Espinet Mestre, Carme
author_role author
author2 Fleitas Pérez, Catherine
Zammou, Bahira
Ferrer, Isidre
Rampon, Claire
Egea Navarro, Joaquim
Espinet Mestre, Carme
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Alzheimer’s disease
Adult neurogenesis
pro-NGF
p75
Dentate gyrus
Memory impairment
topic Alzheimer’s disease
Adult neurogenesis
pro-NGF
p75
Dentate gyrus
Memory impairment
description In recent decades, neurogenesis in the adult brain has been well demonstrated in anumber of animal species, including humans. Interestingly, work with rodents has shown that adultneurogenesis in the dentate gyrus (DG) of the hippocampus is vital for some cognitive aspects, asincreasing neurogenesis improves memory, while its disruption triggers the opposite effect. Adultneurogenesis declines with age and has been suggested to play a role in impaired progressive learningand memory loss seen in Alzheimer’s disease (AD). Therefore, therapeutic strategies designed toboost adult hippocampal neurogenesis may be beneficial for the treatment of AD. The precursor formsof neurotrophins, such as pro-NGF, display remarkable increase during AD in the hippocampusand entorhinal cortex. In contrast to mature NGF, pro-NGF exerts adverse functions in survival,proliferation, and differentiation. Hence, we hypothesized that pro-NGF and its p75 neurotrophinreceptor (p75NTR) contribute to disrupting adult hippocampal neurogenesis during AD. To test thishypothesis, in this study, we took advantage of the availability of mouse models of AD (APP/PS1),which display memory impairment, and AD human samples to address the role of pro-NGF/p75NTRsignaling in different aspects of adult neurogenesis. First, we observed that DG doublecortin (DCX) +progenitors express p75NTR both, in healthy humans and control animals, although the percentageof DCX+ cells are significantly reduced in AD. Interestingly, the expression of p75NTR in theseprogenitors is significantly decreased in AD conditions compared to controls. In order to assessthe contribution of the pro-NGF/p75NTR pathway to the memory deficits of APP/PS1 mice, weinjected pro-NGF neutralizing antibodies (anti-proNGF) into the DG of control and APP/PS1 miceand animals are subjected to a Morris water maze test. Intriguingly, we observed that anti-pro-NGF significantly restored memory performance of APP/PS1 animals and significantly increasethe percentage of DCX+ progenitors in the DG region of these animals. In summary, our resultssuggest that pro-NGF is involved in disrupting spatial memory in AD, at least in part by blockingadult neurogenesis. Moreover, we propose that adult neurogenesis alteration should be taken intoconsideration for better understanding of AD pathology. Additionally, we provide a new molecularentry point (pro-NGF/p75NTR signaling) as a promising therapeutic target in AD.
publishDate 2021
dc.date.none.fl_str_mv 2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://doi.org/10.3390/ijms221910744
http://hdl.handle.net/10459.1/83631
url https://doi.org/10.3390/ijms221910744
http://hdl.handle.net/10459.1/83631
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.3390/ijms221910744 
International Journal of Molecular Sciences, 2021, vol. 22, núm. 19
dc.rights.none.fl_str_mv cc-by (c) Authors, 2021
info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/4.0/
rights_invalid_str_mv cc-by (c) Authors, 2021
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:Repositori Obert UdL
instname:Universitat de Lleida (UdL)
instname_str Universitat de Lleida (UdL)
reponame_str Repositori Obert UdL
collection Repositori Obert UdL
repository.name.fl_str_mv
repository.mail.fl_str_mv
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