PNU282987 alleviates Aβ-induced anxiety and depressive-like behaviors through upregulation of α7nAChR by ERK-serotonin receptors pathway

Patients with Alzheimer's disease often undergo anxiety and depression. Our previous studies have shown that alpha 7nAChR protects against A beta-induced neurotoxicity via downregulation of p38 and JNK MAPKs, but the role of alpha 7nAChR on A beta-induced anxiety and depressive-like behaviors and the effect of alpha 7nAChR on the regulation of MAPKs pathways remain unknown. To examine the effects of alpha 7nAChR and MAPKs pathways on A beta-induced anxiety and depression-like behaviors and to explore their relationships between them, elevated plus maze, open field and forced swim tests were performed. Protein levels of 5-HT1A receptor, 5-HT2C receptor, alpha 7nAChR, t-ERK1/2 and p-ERK1/2 in the amygdala were analyzed by western blotting and immunostaining. Our study found out that A beta oligomers induced anxiety and depression-like behaviors in C56BL/6 mice with open field, elevated plus maze and forced swim tests. However, activation of alpha 7nAChR or inhibition of ERK pathways showed significant antidepressant and anxiolytic-like effects on A beta-injected mice. Moreover, A beta significantly decreased the level of 5-HT1A receptor but increased the level of 5-HT2C receptor in the basolateral amygdala. Treatment with alpha 7nAChR agonist PNU282987 or ERK inhibitor U0126 reversed A beta-induced 5-HT1A and 5-HT2C receptor changes. Moreover, activation of alpha 7nAChR inhibited ERK pathway in the amygdala of A beta(1-42)-injected mice. Our study provides a new insight into the mechanism of alpha 7nAChR in A beta-induced depression and anxiety-related symptoms through the regulation of ERK1/2 pathway and the potential association with serotonin receptors. Together, our data suggests that alpha 7nAChR is protective against A beta-induced anxiety and depression-like behaviors in mice.