Inhibition of GPR17 with cangrelor improves cognitive impairment and synaptic deficits induced by Aβ1–42 through Nrf2/HO-1 and NF-κB signaling pathway in mice

The accumulation of amyloid beta (Aβ) in the brain is thought to be associated with cognitive deficits in Alzheimer's disease (AD). However, current methods to combat Aβ neurotoxicity are still lacking. G protein-coupled receptor 17 (GPR17) has become a target for treating inflammation in brain diseases, but it is unclear whether it has a role in AD. Here, we investigated the effects of cangrelor, a GPR17 antagonist, on neurotoxicity and memory impairment induced by intracerebroventricular (i.c.v.) injection of Aβ1-42 in mice. The behavior results showed that cangrelor (2.0 or 4.0 μg/mouse, i.c.v.) treatment reversed the deficits in memory and learning ability induced by Aβ1-42 in mice. Importantly, we demonstrated for the first time that GPR17 expression in the hippocampus and frontal cortex is increased in response to Aβ1-42 exposures. We also found that cangrelor treatment reduced the activity of β-secretase 1 (BACE1) and the levels of soluble Aβ1-42 in the hippocampus and frontal cortex. Meanwhile, cangrelor treatment suppressed oxidative stress induced by Aβ1-42, as proved by reduced production of malondialdehyde (MDA), and increased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT), and promoted the expression of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1). Furthermore, cangrelor also suppressed Aβ1-42-induced neuroinflammation, characterized by suppressed activation of microglia, decreased the levels of pro-inflammatory cytokines, and nuclear translocation of NF-κB p65, as well as ameliorated synaptic deficits by promoting the upregulation of synaptic proteins, and increasing the number of Golgi-Cox stained dendritic spines. These results suggest that cangrelor may reverse Aβ1-42-induced cognition deficits via inhibiting oxidative stress, neuroinflammation, and synaptic dysfunction mediated by Nrf2/HO-1 and NF-κB signaling.