GW9508 ameliorates cognitive dysfunction via autophagy pathway in streptozotocin‐induced mouse model of Alzheimer's disease

Abstract Background G protein‐coupled receptor 40 (GPR40) is a potential drug target for Alzheimer's disease (AD), and its agonist GW9508 ameliorates cognitive impairment by intravenous administration. Objectives The present study was conducted to investigate the efficacy of GW9508 administered peripherally on cognitive dysfunction in streptozotocin (STZ)‐induced AD mice. Methods Seventy male ICR mice were randomly divided into seven groups: vehicle sham group, model, Donepezil, GW9508‐L, GW9508‐M, GW9508‐H, and GW1100 + GW9508‐H groups, and administered either vehicle (artificial cerebrospinal fluid [aCSF]) or STZ (3 mg/kg in the vehicle) once a day (9:00 a.m.) by intracerebroventricular injection bilaterally on day 1 and day 3, respectively. After 2 weeks of recovery, all mice were given drug treatment. Behavioral experiments were applied to test the recognition and spatial memory of mice, while molecular biology experiments such as Western blot, ELISA, and Nissl staining were used to detect the corresponding changes of signaling pathways. Results Intraperitoneal administration of GW9508 prevented STZ‐induced cognitive impairment as well as decreased the level of p‐tau and Aβ 1–42 in plasma and brain. GW9508 upregulated the expression of gut‐brain peptides like PYY, CCK, IGF‐1, and GLP‐1 both in blood circulation and brain and downregulated the expression level of autophagy‐related proteins through activating Akt/mTOR signaling pathway. Meanwhile, the treatment effect of GW9508 was reversed by GPR40 antagonist GW1100 significantly. Conclusion Peripheral administration of GW9508 exhibits neuroprotective effects, and it could be a promising therapy for AD. The neuroprotective mechanism of GW9508 was based on promoting gut‐brain peptide secretion, activating Akt/mTOR signal pathway, and regulating neuronal autophagy.