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.