Activation of GPR55 attenuates cognitive impairment, oxidative stress, neuroinflammation, and synaptic dysfunction in a streptozotocin-induced Alzheimer's mouse model.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cascading changes in cognition and behavior. G-protein-coupled receptor 55 (GPR55) has been used as a promising target for the treatment of diabetes, but its function in AD is unclear. The objective of this study was to investigate the neuroprotective effects of O-1602, a GPR55 agonist, on the streptozotocin (STZ)-induced AD mouse model. A single intracerebroventricular (i.c.v.) injection of STZ into the brains of mice significantly induced cognitive impairment. In contrast, O-1602 (2.0 or 4.0 μg/mouse, i.c.v.) can improve the cognitive dysfunction caused by STZ in the Morris water maze (MWM) and novel object recognition (NOR) tests. Importantly, O-1602 treatment reversed STZ-induced GPR55 down-regulation, reduced the activity of β-secretase 1 (BACE1) and the level of Aβ, and abolished the up-regulation of acetylcholinesterase (AChE) activity in the hippocampus and frontal cortex. Besides, O-1602 markedly suppressed STZ-induced oxidative stress, characterized by decreased malondialdehyde (MDA) level, and increased the levels of glutathione (GSH), superoxide dismutases (SOD), and catalase (CAT), as well as attenuated neuroinflammation as indicated by decreased series of pro-inflammatory cytokines and microglia activation. O-1602 treatment also ameliorated synaptic dysfunction by promoting the up-regulation of PSD-95 protein in the STZ-treated mice. Our results suggest that O-1602 has potent neuroprotective effects against STZ-induced neurotoxicity. Meanwhile, these findings suggest that GPR55 might be a novel and promising target for the treatment of AD.