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 pharmacological targets, such as the endocannabinoid system (ECS), are being explored. Previous results from our laboratory showed a TAU^P301L-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 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 CB₂ antagonist treatment against TAU-associated FTD.