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.

Abstract The accumulation of amyloid-β (Aβ) peptides in the brain is considered to be the initial event in the Alzheimer's disease (AD). Neurotoxicity mediated by Aβ 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 Aβ1–42 (400 pmol/mouse) in mice. Our results showed that i.c.v. injection of aggregated Aβ1–42 into the brain of mice resulted in cognitive impairment and neurotoxicity. In contrast, O-1602 (2.0 or 4.0 μg/mouse, i.c.v.) can improve memory impairment induced by Aβ1–42 in the Morris water maze (MWM), and novel object recognition (NOR) tests. Besides, we found that O-1602 reduced the activity of β-secretase 1 (BACE1) and the level of soluble Aβ1–42 in the hippocampus and frontal cortex. Importantly, O-1602 treatment reversed Aβ1–42-induced GPR55 down-regulation, 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 Aβ1–42-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.