GW9508 ameliorates cognitive impairment via the cAMP-CREB and JNK pathways in APPswe/PS1dE9 mouse model of Alzheimer's disease

GPR40 was utilized as the drug target to the treatment of diabetes, but the function and mechanisms ameliorating the Alzheimer's disease (AD) remain unknown. In present study, the typical APP/PS1 mouse model was applied to explore the function and mechanism of GPR40 in AD. GPR40 agonist GW9508 and antagonist GW1100 were respectively given by i.c.v. injection to activate/inhibit the GPR40 in the brain of APP/PS1 mice which illustrated the function and mechanism of GPR40 in ameliorating AD symptoms. Morris water maze test, step-through test, Y-maze spontaneous alternation test, open field test and new object recognition test were used to test the cognitive function and memory ability of mice, while Molecular Biology experiments such as Western blot, immunofluorescence, JC-1 were used to detect the corresponding changes of signal pathways. The results revealed that treatment with GW9508 could significantly ameliorate cognitive deficits of APP/PS1 mice, upregulate the expression levels of cAMP, p-CREB and Neurotrophic Factors in vivo, while GW9508 also ameliorate Aβ_1-42-induced neuron damage and downregulate the expression levels of pathological protein such as p-JNK, JNK and apoptosis-related proteins such as IL-6, IL-1β, TNF-α and Caspase-3 in vitro. Meanwhile, high-content screening also showed that GW9508 promoted the cellular differentiation of SH-SY5Y cells, while GW1100 reversed the effects of GW9508. These results suggested that GPR40 was an underlying therapeutic target for the treatment of AD and GPR40 agonist could be explored as the emerging AD therapeutic drug.