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

Abstract

Patients with Alzheimer's disease often undergo anxiety and depression. Our previous studies have shown that α7nAChR protects against Aβ-induced neurotoxicity via downregulation of p38 and JNK MAPKs, but the role of α7nAChR on Aβ-induced anxiety and depressive-like behaviors and the effect of α7nAChR on the regulation of MAPKs pathways remain unknown. To examine the effects of α7nAChR and MAPKs pathways on Aβ-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-HT_1A receptor, 5-HT_2C receptor, α7nAChR, t-ERK1/2 and p-ERK1/2 in the amygdala were analyzed by western blotting and immunostaining. Our study found out that Aβ oligomers induced anxiety and depression-like behaviors in C56BL/6 mice with open field, elevated plus maze and forced swim tests. However, activation of α7nAChR or inhibition of ERK pathways showed significant antidepressant and anxiolytic-like effects on Aβ-injected mice. Moreover, Aβ significantly decreased the level of 5-HT_1A receptor but increased the level of 5-HT_2C receptor in the basolateral amygdala. Treatment with α7nAChR agonist PNU282987 or ERK inhibitor U0126 reversed Aβ-induced 5-HT_1A and 5-HT_2C receptor changes. Moreover, activation of α7nAChR inhibited ERK pathway in the amygdala of Aβ_1-42-injected mice. Our study provides a new insight into the mechanism of α7nAChR in Aβ-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 α7nAChR is protective against Aβ-induced anxiety and depression-like behaviors in mice.

Keywords: Alzheimer’s disease; Anxiety; Depression; ERK MAPK signaling pathway; α7nAChR.