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Analysis of institutional authors

Silva-Llanes, IgnacioAuthorLopez, Manuela GAuthorLastres-Becker, IsabelCorresponding Author

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April 28, 2025
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Targeting CB2 receptor with a novel antagonist reverses cognitive decline, neurodegeneration and pyroptosis in a TAU-dependent frontotemporal dementia mouse model

Publicated to: Brain Behavior And Immunity. 127 251-268 - 2025-07-01 127(), DOI: 10.1016/j.bbi.2025.03.008

Authors:

Silva-Llanes, Ignacio; Rodriguez-Lopez, Silvia; Gonzalez-Naranjo, Pedro; del Sastre, Eric; Lopez, Manuela G; Paez, Juan Antonio; Campillo, Nuria; Lastres-Becker, Isabel
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Affiliations

CSIC, Ctr Invest Biol Margarita Salas, Ramiro Maeztu 9, Madrid 28040, Spain - Author
CSIC, Inst Quim Med, Juan De La Cierva 3, Madrid 28006, Spain - Author
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Madrid, Spain - Author
Ctr Invest Canc, Campus Miguel De Unamuno, Salamanca 37007, Spain - Author
Inst Invest Sanitaria La Paz IdiPaz, Madrid, Madrid, Spain - Author
UAM, Inst Invest Biomed Sols Morreale, CSIC, Madrid, Spain - Author
Univ Autonoma Madrid UAM, Sch Med, Dept Biochem, Madrid, Spain - Author
Univ Autonoma Madrid, Fac Med, Dept Farmacol & Terapeut, Madrid 28029, Spain - Author
Univ Autonoma Madrid, Inst Teofilo Hernando, Madrid 28029, Spain - Author
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Abstract

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 TAUP301L-dependent increase in CB2 receptor expression in hippocampal neurons of a FTD mouse model, alongside the neuroprotective impact of CB2 ablation. In this study, we evaluated the therapeutic potential of a new CB2 antagonist (PGN36) in our TAU-dependent FTD mouse model. Six-month-old mice received stereotaxic injections of an adeno-associated virus expressing human TAUP301L protein (AAV-TAUP301L) 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 TAUP301L overexpression. PGN36 treatment effectively countered TAUP301L-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 TAUP301L 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 CB2 antagonist treatment against TAU-associated FTD.
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Keywords

ActivatioAdenylyl-cyclaseAlzheimers-diseaseCb 2 antagonistsCb(2) antagonistsCb2 antagonistsEndocannabinoid systemEntorhinal cortexFtdGasderminGasdermin dHippocampalIn-vitroLobar degenerationNeurodegenerationNeuroinflammationPeripheral cannabinoid receptorPyroptosisSr 144528Tau

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal BRAIN BEHAVIOR AND IMMUNITY due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2025, it was in position 12/288, thus managing to position itself as a Q1 (Primer Cuartil), in the category Psychiatry.

Independientemente del impacto esperado determinado por el canal de difusión, es importante destacar el impacto real observado de la propia aportación.

Según las diferentes agencias de indexación, el número de citas acumuladas por esta publicación hasta la fecha 2026-04-09:

  • WoS: 1
  • Scopus: 1
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Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2026-04-09:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 5.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 5 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 22.
  • The number of mentions on the social network X (formerly Twitter): 3 (Altmetric).
  • The number of mentions in news outlets: 2 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

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Leadership analysis of institutional authors

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (SILVA LLANES, IGNACIO) and Last Author (LASTRES BECKER, ISABEL).

the author responsible for correspondence tasks has been LASTRES BECKER, ISABEL.

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Awards linked to the item

This work was supported by Fundacion Tatiana Perez de Guzman el Bueno, MINECO (grants PID2019-105600RB-I00 and PID2022137065OB-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.
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