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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
Ignacio Silva-Llanes, Silvia Rodríguez-López, Pedro González-Naranjo, Eric del Sastre, Manuela G. López, Juan Antonio Paez, Nuria Eugenia Campillo, Isabel Lastres‐Becker. Brain Behavior and Immunity, 2025-03-11
Topic: Brain proteins, microglia and lab models
• The new CB 2 antagonist PGN36 is able to cross the Blood-Brain Barrier. • PGN36 treatment effectively alleviates TAU P301L -induced cognitive decline . • PGN36 is able to reduce TAU protein expression levels and restore synaptic plasticity. • PGN36 modulates TAU P301L -induced pyroptosis. 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 P301L -dependent increase in CB 2 receptor expression in hippocampal neurons of a FTD mouse model, alongside the neuroprotective impact of CB 2 ablation. In this study, we evaluated the therapeutic potential of a new CB 2 antagonist (PGN36) in our TAU-dependent FTD mouse model. Six-month-old mice received stereotaxic injections of an adeno-associated virus expressing human TAU P301L protein (AAV-TAU P301L ) 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 P301L overexpression. PGN36 treatment effectively countered TAU P301L -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 P301L 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 2 antagonist treatment against TAU-associated FTD.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Silva-Llanes, I., Rodríguez-López, S., González-Naranjo, P., del Sastre, E., López, M. G., Paez, J. A., et al. (2025). Targeting CB2 receptor with a novel antagonist reverses cognitive decline, neurodegeneration and pyroptosis in a TAU-dependent frontotemporal dementia mouse model. Brain Behavior and Immunity. https://doi.org/10.1016/j.bbi.2025.03.008
Vancouver
Silva-Llanes I, Rodríguez-López S, González-Naranjo P, del Sastre E, López MG, Paez JA, et al. Targeting CB2 receptor with a novel antagonist reverses cognitive decline, neurodegeneration and pyroptosis in a TAU-dependent frontotemporal dementia mouse model. Brain Behavior and Immunity. 2025. doi:10.1016/j.bbi.2025.03.008. PMID: 40081780.
BibTeX
@article{silvallanes2025-40081780,
author = {Silva-Llanes, Ignacio and Rodríguez-López, Silvia and González-Naranjo, Pedro and del Sastre, Eric and López, Manuela G. and Paez, Juan Antonio and Campillo, Nuria Eugenia and Lastres‐Becker, Isabel},
title = {{Targeting CB2 receptor with a novel antagonist reverses cognitive decline, neurodegeneration and pyroptosis in a TAU-dependent frontotemporal dementia mouse model}},
journal = {Brain Behavior and Immunity},
year = {2025},
doi = {10.1016/j.bbi.2025.03.008},
pmid = {40081780},
url = {https://doi.org/10.1016/j.bbi.2025.03.008}
}
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record names 8 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
Key findings
- Previous results from our laboratory showed a TAU P301L -dependent increase in CB 2 receptor expression in hippocampal neurons of a FTD mouse model, alongside the neuroprotective impact of CB 2 ablation.
- 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 P301L overexpression.
- Notably, we observed neuroprotection in the dentate gyrus granular layer, which we attribute to the modulation of pyroptosis.
- These findings collectively underscore the neuroprotective potential of this novel CB 2 antagonist treatment against TAU-associated FTD.
Why it matters
In a mouse model expressing human TAU P301L, treatment with the new CB2 receptor antagonist PGN36 alleviated cognitive decline, reduced TAU protein levels, restored synaptic plasticity and modulated pyroptosis. These findings are from an animal model of frontotemporal dementia and do not establish a treatment, cure or prevention for Alzheimer's disease.
Study details
- Evidence strengthLow
How this study scored 41/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Brain Behavior and Immunity) |
| Journal's citation record | 2 / 4 | Brain Behavior and Immunity: journal h-index 249 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “mouse”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 8 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 2.7 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 4.4× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 1 other studies in this library |
| Still being cited | 1 / 4 | Cited 8 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Isabel Lastres‐Becker: h-index 40 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Consejo Superior de Investigaciones Científicas: institution h-index 1,048 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 8 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40081780) |
| Free to read | 2 / 2 | Free to read |
| Total | 41 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1016/j.bbi.2025.03.008
- PubMed: 40081780
- Original source →
- Free full text: Brain Behavior and Immunity →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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