Neuroprotective effects induced by NR2A-CB1R and NR2B-CB1R complexes in Alzheimer's disease

Despite extensive research, effective treatment for Alzheimer’s disease (AD) remains elusive. Emerging evidence suggests that the endocannabinoid system and glutamatergic neurotransmission play important roles in AD pathophysiology. This project aims to elucidate the involvement of cannabinoid type 1 receptor (CB1R) on regulating the cytotoxic effects induced by N-methyl-D-aspartate receptors (NMDARs) in AD. On the one hand, CB1R activation reduces neuroinflammation and promotes neuroprotection in AD models. On the other hand, the synaptic receptor NR2A contribute to synaptic integrity and memory development. It has been observed that Aβ specifically activate extrasynaptic NMDARs exacerbating synaptic dysfunction and neurodegeneration in AD brains. Also, the extrasynaptic NMDAR containing NR2B subunit induces neurotoxicity and excitotoxicity. Emerging evidence suggests a complex interplay between CB1R and NMDARs. At the functional level, it has been observed a negative cross-talk induced by CB1R in the NR2B signaling in transfected HEK-293T cells. It has also been demonstrated a potentiation of the endocannabinoid signaling by the presence of NMDAR containing NR2A subunit in comparison with NR2B in transfected HEK-293T and cortical neurons. This effect is also observed in the AD 5XFAD mice model. However, the activation of the NMDAR containing NR2B subunit in the presence of the Aβ peptide downregulates the CB1 receptor functionality. Finally, in 5XFAD mice model, it has been demonstrated a decrease in p-Tau mobilization by CB1R activation in neurons KO for the NR2B subunit. Taken together, these results point that future research should focus on elucidating CB1-NMDAR interactions and evaluating new therapies in AD patients.