Implications of CB2 cannabinoid receptors in the neurodegenerative process associated to tauopathies

Abstract

[Background] Tauopathies are a group of neurodegenerative diseases characterized by the aggregation of TAU protein for which there is no effective treatment yet. This is the reason why new approaches are now being investigated, such as the endocannabinoid system. In Alzheimer’s disease, it has been shown that the levels of type-2 cannabinoid receptors (CB2) are increased in the glial cells that surround amyloid plaques. Nevertheless, the effects that TAU accumulation has on CB2 expression and its implication in the neurodegenerative process are still unknown.

[Results] We have seen an increase in CB2 expression in hippocampal neurons of 12 month-old transgenic mice overexpressing hTAUP301S protein. This alteration is an early event on the pathology, as CB2 levels are also increased in another animal model overexpressing hTAUP301L where there is not neuronal death. Moreover, CB2 expression in these mice can be modulated by dimethyl fumarate (DMF) treatment, an NRF2 inductor with neuroprotective effects. These results were reproduced in vitro when hTAUP301L was overexpressed in HT22 cells. Finally, we found an antioxidant response element on CNR2 promoter and our analysis in vitro point out at the possibility that CB2 expression could be modulated by NRF2.

[Conclusions] Overexpression of hTAU protein increases CB2 levels in neurons and can be modulated by DMF treatment.