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

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

  • Brain Behav Immun. 2025 Mar 11:127:251-268. doi: 10.1016/j.bbi.2025.03.008.
Ignacio Silva-Llanes 1,  Silvia Rodríguez-López 2,  Pedro González-Naranjo 3,  Eric Del Sastre 4,  Manuela G López 5,  Juan Antonio Páez 6,  Nuria Campillo 7,  Isabel Lastres-Becker 8
Affiliations

Affiliations

  • 1 Department of Biochemistry, School of Medicine, Universidad Autónoma de Madrid (UAM), Spain; Instituto de Investigaciones Biomédicas "Sols-Morreale" UAM-CSIC, Madrid, Spain; Instituto de Investigación Sanitaria La Paz (IdiPaz), Madrid, Madrid, Spain. Electronic address: ignaciosilva@iib.uam.es.
  • 2 Department of Biochemistry, School of Medicine, Universidad Autónoma de Madrid (UAM), Spain; Instituto de Investigaciones Biomédicas "Sols-Morreale" UAM-CSIC, Madrid, Spain. Electronic address: silviamaria.rodriguezlopez@gmail.com.
  • 3 Instituto de Química Médica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain. Electronic address: pedrojgn@iqm.csic.es.
  • 4 Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid 28029 Madrid, Spain. Electronic address: ericdelsastre@gmail.com.
  • 5 Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid 28029 Madrid, Spain. Electronic address: manuela.garcia@uam.es.
  • 6 Instituto de Química Médica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain. Electronic address: jpaez@iqm.csic.es.
  • 7 Centro de Investigaciones Biológicas Margarita Salas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain. Electronic address: nuria.campillo@csic.es.
  • 8 Department of Biochemistry, School of Medicine, Universidad Autónoma de Madrid (UAM), Spain; Instituto de Investigaciones Biomédicas "Sols-Morreale" UAM-CSIC, Madrid, Spain; Instituto de Investigación Sanitaria La Paz (IdiPaz), Madrid, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Madrid, Spain. Electronic address: ilbecker@iib.uam.es.
PMID: 40081780 DOI: 10.1016/j.bbi.2025.03.008
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.

Keywords

CB(2) antagonists; FTD; GASDERMIN D; Neurodegeneration; Neuroinflammation; Pyroptosis; TAU.

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