Inactivation of the CB2 receptor accelerated the neuropathological deterioration in TDP-43 transgenic mice, a model of amyotrophic lateral sclerosis

The activation of the cannabinoid receptor type-2 (CB2) afforded neuroprotection in amyotrophic lateral sclerosis (ALS) models. The objective of this study was to further investigate the relevance of the CB2 receptor through investigating the consequences of its inactivation. TDP-43(A315T) transgenic mice were crossed with CB2 receptor knock-out mice to generate double mutants. Temporal and qualitative aspects of the pathological phenotype of the double mutants were compared to TDP-43 transgenic mice expressing the CB2 receptor. The double mutants exhibited significantly accelerated neurological decline, such that deteriorated rotarod performance was visible at 7 weeks, whereas rotarod performance was normal up to 11 weeks in transgenic mice with intact expression of the CB2 receptor. A morphological analysis of spinal cords confirmed an earlier death (visible at 65 days) of motor neurons labelled with Nissl staining and ChAT immunofluorescence in double mutants compared to TDP-43 transgenic mice expressing the CB2 receptor. Evidence of glial reactivity, measured using GFAP and Iba-1 immunostaining, was seen in double mutants at 65 days, but not in TDP-43 transgenic mice expressing the CB2 receptor. However, at 90 days, both genotypes exhibited similar changes for all these markers, although surviving motor neurons of transgenic mice presented some morphological abnormalities in absence of the CB2 receptor that were not as evident in the presence of this receptor. This faster deterioration seen in double mutants led to premature mortality compared with TDP-43 transgenic mice expressing the CB2 receptor. We also investigated the consequences of a pharmacological inactivation of the CB2 receptor using the selective antagonist AM630 in TDP-43 transgenic mice, but results showed only subtle trends towards a greater deterioration. In summary, our results confirmed the potential of the CB2 receptor agonists as a neuroprotective therapy in ALS and strongly support the need to progress towards an evaluation of this potential in patients.

Automated summary

The activation of the cannabinoid receptor type-2 (CB2) has neuroprotective effects in ALS models, while the inactivation of CB2 receptor leads to accelerated deterioration and premature mortality in TDP-43 transgenic mice. Pharmacological inactivation of CB2 receptor also showed subtle trends towards worsening ALS symptoms. These findings suggest the potential of CB2 receptor agonists as a neuroprotective therapy for ALS.