Activation of GPR55 attenuates cognitive impairment and neurotoxicity in a mouse model of Alzheimer's disease induced by Aβ1-42 through inhibiting RhoA/ROCK2 pathway

The accumulation of amyloid-beta (A beta) peptides in the brain is considered to be the initial event in the Alzheimer's disease (AD). Neurotoxicity mediated by A beta has been demonstrated to damage the cognitive function. In the present study, we sought to determine the effects of O-1602, a specific G-protein coupled receptor 55 (GPR55) agonist, on the impairment of learning and memory induced by intracerebroventricular (i.c.v.) of A beta(1-42) (4.0 mu g/mouse) in mice. Our results showed that i.c.v. injection of aggregated A beta(1-42) into the brain of mice resulted in cognitive impairment and neurotoxicity. In contrast, O-1602 (2.0 or 4.0 mu g/mouse, i.c.v.) can improve memory impairment induced by A beta(1-42) in the Morris water maze (MWM), and novel object recognition (NOR) tests. Besides, we found that O-1602 reduced the activity of p-secretase 1 (BACE1) and the level of soluble A beta(1-42) in the hippocampus and frontal cortex. Importantly, O-1602 treatment reversed A beta(1-42)-induced GPR55 downregulation, decreased pro-inflammatory cytokines, and the level of malondialdehyde (MDA), increased the levels of glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT), as well as suppressed apoptosis as indicated by decreased TUNEL-positive cells, and increased the ratio of Bcl-2/Bax. O-1602 treatment also pronouncedly ameliorated synaptic dysfunction by promoting the upregulation of PSD-95 and synaptophysin (SYN) proteins. Moreover, O-1602 concurrently down regulated the protein levels of RhoA, and ROCK2, the critical proteins in the RhoA/ROCK2 pathway. This study indicates that O-1602 may reverse A beta(1-42)-induced cognitive impairment and neurotoxicity in mice by inhibiting RhoA/ROCK2 pathway. Taken together, these findings suggest that GPR55 could be a novel and promising target for the treatment of AD.

Automated summary

The study shows that O-1602 can reverse cognitive impairment and neurotoxicity induced by A beta(1-42) by inhibiting the RhoA/ROCK2 pathway, suggesting that GPR55 could be a novel and promising target for the treatment of Alzheimer's disease.