Targeting CB2 receptor with a novel antagonist reverses cognitive decline, neurodegeneration and pyroptosis in a TAU-dependent frontotemporal dementia mouse model

Frontotemporal dementia (FTD) comprises a group of disorders characterized by a progressive decline in behavior or language linked to the degeneration of the frontal and anterior temporal lobes followed by hippocampal atrophy. There are no effective treatments for FTD and for this reason, novel phar...

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Autores: Silva-Llanes, Ignacio, Rodríguez-López, S., González-Naranjo, Pedro, Sastre, E. del, López, Manuela G., Páez, Juan A., Campillo, Nuria, Lastres-Becker, Isabel
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/387861
Acesso em linha:http://hdl.handle.net/10261/387861
Access Level:acceso abierto
Palavra-chave:CB2 antagonists
TAU
FTD
Neurodegeneration
Neuroinflammation
Pyroptosis
GASDERMIN D
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spelling Targeting CB2 receptor with a novel antagonist reverses cognitive decline, neurodegeneration and pyroptosis in a TAU-dependent frontotemporal dementia mouse modelSilva-Llanes, IgnacioRodríguez-López, S.González-Naranjo, PedroSastre, E. delLópez, Manuela G.Páez, Juan A.Campillo, NuriaLastres-Becker, IsabelCB2 antagonistsTAUFTDNeurodegenerationNeuroinflammationPyroptosisGASDERMIN DFrontotemporal dementia (FTD) comprises a group of disorders characterized by a progressive decline in behavior or language linked to the degeneration of the frontal and anterior temporal lobes followed by hippocampal atrophy. There are no effective treatments for FTD and for this reason, novel pharmacological targets, such as the endocannabinoid system (ECS), are being explored. Previous results from our laboratory showed a TAU-dependent increase in CB receptor expression in hippocampal neurons of a FTD mouse model, alongside the neuroprotective impact of CB ablation. In this study, we evaluated the therapeutic potential of a new CB antagonist (PGN36) in our TAU-dependent FTD mouse model. Six-month-old mice received stereotaxic injections of an adeno-associated virus expressing human TAU protein (AAV-TAU) into the right hippocampus and were treated daily with PGN36 (5 mg/kg, i.p.) or vehicle for three weeks. By integrating behavioral tests, RNA-seq, qPCR expression analysis, and immunofluorescence in the AAV expressing TAU mouse model, we found that PGN36 treatment reverses key features of the neurodegenerative process triggered by TAU overexpression. PGN36 treatment effectively countered TAU-induced cognitive decline by reducing TAU protein expression levels and restoring markers of synaptic plasticity. Notably, we observed neuroprotection in the dentate gyrus granular layer, which we attribute to the modulation of pyroptosis. This programmed cell death pathway, is triggered by TAU overexpression. PGN36 appears to modulate the pyroptotic cascade, thereby preventing the pyroptosis-induced neuronal loss. These findings collectively underscore the neuroprotective potential of this novel CB antagonist treatment against TAU-associated FTD.This work was supported by Fundación Tatiana Pérez de Guzmán el Bueno, MINECO (grants PID2019-105600RB-I00 and PID2022- 137065OB-I00 to I.L-B and PDC2022-133809-I00 to MGL), ISCiii CIBERNED (CB06/05/0089 to I. L-B.) and Community of Madrid ref CAM-P2022/BMD-7230 to MGL. FPU18/00630 contract to ES.ElsevierFundación Tatiana Pérez de Guzmán el BuenoMinisterio de Ciencia e Innovación (España)Comunidad de MadridConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2025202520252025info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/387861reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-105600RB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-137065OB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PDC2022-133809-I00http://dx.doi.org/10.1016/j.bbi.2025.03.008Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3878612026-05-22T06:33:51Z
dc.title.none.fl_str_mv Targeting CB2 receptor with a novel antagonist reverses cognitive decline, neurodegeneration and pyroptosis in a TAU-dependent frontotemporal dementia mouse model
title Targeting CB2 receptor with a novel antagonist reverses cognitive decline, neurodegeneration and pyroptosis in a TAU-dependent frontotemporal dementia mouse model
spellingShingle Targeting CB2 receptor with a novel antagonist reverses cognitive decline, neurodegeneration and pyroptosis in a TAU-dependent frontotemporal dementia mouse model
Silva-Llanes, Ignacio
CB2 antagonists
TAU
FTD
Neurodegeneration
Neuroinflammation
Pyroptosis
GASDERMIN D
title_short Targeting CB2 receptor with a novel antagonist reverses cognitive decline, neurodegeneration and pyroptosis in a TAU-dependent frontotemporal dementia mouse model
title_full Targeting CB2 receptor with a novel antagonist reverses cognitive decline, neurodegeneration and pyroptosis in a TAU-dependent frontotemporal dementia mouse model
title_fullStr Targeting CB2 receptor with a novel antagonist reverses cognitive decline, neurodegeneration and pyroptosis in a TAU-dependent frontotemporal dementia mouse model
title_full_unstemmed Targeting CB2 receptor with a novel antagonist reverses cognitive decline, neurodegeneration and pyroptosis in a TAU-dependent frontotemporal dementia mouse model
title_sort Targeting CB2 receptor with a novel antagonist reverses cognitive decline, neurodegeneration and pyroptosis in a TAU-dependent frontotemporal dementia mouse model
dc.creator.none.fl_str_mv Silva-Llanes, Ignacio
Rodríguez-López, S.
González-Naranjo, Pedro
Sastre, E. del
López, Manuela G.
Páez, Juan A.
Campillo, Nuria
Lastres-Becker, Isabel
author Silva-Llanes, Ignacio
author_facet Silva-Llanes, Ignacio
Rodríguez-López, S.
González-Naranjo, Pedro
Sastre, E. del
López, Manuela G.
Páez, Juan A.
Campillo, Nuria
Lastres-Becker, Isabel
author_role author
author2 Rodríguez-López, S.
González-Naranjo, Pedro
Sastre, E. del
López, Manuela G.
Páez, Juan A.
Campillo, Nuria
Lastres-Becker, Isabel
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Fundación Tatiana Pérez de Guzmán el Bueno
Ministerio de Ciencia e Innovación (España)
Comunidad de Madrid
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv CB2 antagonists
TAU
FTD
Neurodegeneration
Neuroinflammation
Pyroptosis
GASDERMIN D
topic CB2 antagonists
TAU
FTD
Neurodegeneration
Neuroinflammation
Pyroptosis
GASDERMIN D
description Frontotemporal dementia (FTD) comprises a group of disorders characterized by a progressive decline in behavior or language linked to the degeneration of the frontal and anterior temporal lobes followed by hippocampal atrophy. There are no effective treatments for FTD and for this reason, novel pharmacological targets, such as the endocannabinoid system (ECS), are being explored. Previous results from our laboratory showed a TAU-dependent increase in CB receptor expression in hippocampal neurons of a FTD mouse model, alongside the neuroprotective impact of CB ablation. In this study, we evaluated the therapeutic potential of a new CB antagonist (PGN36) in our TAU-dependent FTD mouse model. Six-month-old mice received stereotaxic injections of an adeno-associated virus expressing human TAU protein (AAV-TAU) into the right hippocampus and were treated daily with PGN36 (5 mg/kg, i.p.) or vehicle for three weeks. By integrating behavioral tests, RNA-seq, qPCR expression analysis, and immunofluorescence in the AAV expressing TAU mouse model, we found that PGN36 treatment reverses key features of the neurodegenerative process triggered by TAU overexpression. PGN36 treatment effectively countered TAU-induced cognitive decline by reducing TAU protein expression levels and restoring markers of synaptic plasticity. Notably, we observed neuroprotection in the dentate gyrus granular layer, which we attribute to the modulation of pyroptosis. This programmed cell death pathway, is triggered by TAU overexpression. PGN36 appears to modulate the pyroptotic cascade, thereby preventing the pyroptosis-induced neuronal loss. These findings collectively underscore the neuroprotective potential of this novel CB antagonist treatment against TAU-associated FTD.
publishDate 2025
dc.date.none.fl_str_mv 2025
2025
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/387861
url http://hdl.handle.net/10261/387861
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-105600RB-I00
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-137065OB-I00
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PDC2022-133809-I00
http://dx.doi.org/10.1016/j.bbi.2025.03.008
Sí
dc.rights.none.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:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
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