Modulation of the MAPKs pathways affects Aß-induced cognitive deficits in Alzheimer's disease via activation of α7nAChR.

Cognitive impairment in Alzheimer's disease (AD) is characterized by being deficient at learning and memory. Aß1-42 oligomers have been shown to impair rodent cognitive function. We previously demonstrated that activation of α7nAChR, inhibition of p38 or JNK could alleviate Aß-induced memory deficits in Y maze test. In this study, we investigated whether the effects of α7nAChR and MAPKs on Y maze test is reproducible with a hippocampus-dependent spatial memory test such as Morris water maze. We also assessed the possible co-existence of hippocampus-independent recognition memory dysfunction using a novel object recognition test and an alternative and stress free hippocampus-dependent recognition memory test such as the novel place recognition. Besides, previous research from our lab has shown that MAPKs pathways regulate Aß internalization through mediating α7nAChR. In our study, whether MAPKs pathways exert their functions in cognition by modulating α7nAChR through regulating glutamate receptors and synaptic protein, remain little known. Our results showed that activation of α7nAChR restored spatial memory, novel place recognition memory, and short-term and long-term memory in novel object recognition. Inhibition of p38 restored spatial memory and short-term and long-term memory in novel object recognition. Inhibition of ERK restored short-term memory in novel object recognition and novel place recognition memory. Inhibition of JNK restored spatial memory, short-term memory in novel object recognition and novel place recognition memory. Beside this, the activation of α7nAChR, inhibition of p38 or JNK restored Aß-induced levels of NMDAR1, NMDAR2A, NMDAR2B, GluR1, GluR2 and PSD95 in Aß-injected mice without influencing synapsin 1. In addition, these treatments also recovered the expression of acetylcholinesterase (AChE). Finally, we found that the inhibition of p38 or JNK resulted in the upregulation of α7nAChR mRNA levels in the hippocampus. Our results indicated that inhibition of p38 or JNK MAPKs could alleviate Aß-induced spatial memory deficits through regulating activation of α7nAChR via recovering memory-related proteins. Moreover, p38, ERK and JNK MAPKs exert different functions in spatial and recognition memory.

PNU282987 alleviates Aß-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 α7nAChR protects against Aß-induced neurotoxicity via downregulation of p38 and JNK MAPKs, but the role of α7nAChR on Aß-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 Aß-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, α7nAChR, t-ERK1/2 and p-ERK1/2 in the amygdala were analyzed by western blotting and immunostaining. Our study found out that Aß 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 Aß-injected mice. Moreover, Aß significantly decreased the level of 5-HT1A receptor but increased the level of 5-HT2C receptor in the basolateral amygdala. Treatment with α7nAChR agonist PNU282987 or ERK inhibitor U0126 reversed Aß-induced 5-HT1A and 5-HT2C receptor changes. Moreover, activation of α7nAChR inhibited ERK pathway in the amygdala of Aß1-42-injected mice. Our study provides a new insight into the mechanism of α7nAChR in Aß-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 Aß-induced anxiety and depression-like behaviors in mice.