- The research group led by Isabel Lastres-Becker has identified a novel compound with neuroprotective effects in preclinical murine models of frontotemporal dementia
- This study paves the way for future therapies targeting TAU‐associated diseases, which currently lack effective treatments
A team from the Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM, CSIC-UAM), headed by Dr. Isabel Lastres-Becker, in collaboration with Dr. Nuria Campillo of the Centro de Investigaciones Biológicas Margarita Salas (CIB, CSIC), and Dr. Manuela García from the Department of Pharmacology at UAM, has published in the journal Brain, Behavior and Immunity a paper on the endocannabinoid system as a potential therapeutic target against frontotemporal dementia (FTD). In it, they developed and evaluated a new compound, PGN36, which acts as an antagonist of the CB2 receptor (cannabinoid receptor type 2).
“In previous studies we observed an aberrant increase in CB2 receptor expression in hippocampal neurons of FTD models, as well as a neuroprotective effect upon removal of this receptor,” explains Dr. Lastres-Becker. “These findings led us to explore the effects of its blockade using a specific antagonist.”
PGN36 Reverses Cognitive Impairment and Protects Against Neuronal Inflammation
The results demonstrated that treatment with PGN36 yields several beneficial effects: it counteracts the cognitive decline induced by abnormal TAU protein accumulation, reduces expression of this pathological protein in the brain, restores synaptic plasticity markers essential for neuronal function, and provides neuroprotection in key hippocampal regions.
One of the most striking findings was PGN36’s effect on pyroptosis, an inflammatory form of cell death associated with neurodegenerative diseases. “Overexpression of the TAUP301L variant activates this inflammatory pathway, leading to neuronal death. Our compound appears to modulate this process, which could prevent neuron loss,” details Dr. Lastres-Becker.
Although the results are encouraging, the authors emphasize that further studies are needed to confirm the compound’s efficacy and safety before proceeding to human clinical trials.
This work represents a significant advance in the search for treatments for FTD and, potentially, other TAU‐related diseases. Moreover, it highlights the value of scientific collaboration and the exploration of alternative therapeutic pathways, such as the endocannabinoid system, in a context where available options remain very limited.
Silva-Llanes I, Rodríguez-López S, González-Naranjo P, Sastre ED, López MG, Páez JA, Campillo N, Lastres-Becker I. 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. Epub ahead of print. PMID: 40081780.