Chang_2020_Neurobiol.Learn.Mem__107154

Cognitive impairment in Alzheimer's disease (AD) is characterized by being deficient at learning and memory. Abeta1-42 oligomers have been shown to impair rodent cognitive function. We previously demonstrated that activation of alpha7nAChR, inhibition of p38 or JNK could alleviate Abeta-induced memory deficits in Y maze test. In this study, we investigated whether the effects of alpha7nAChR 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 Abeta internalization through mediating alpha7nAChR. In our study, whether MAPKs pathways exert their functions in cognition by modulating alpha7nAChR through regulating glutamate receptors and synaptic protein, remain little known. Our results showed that activation of alpha7nAChR 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 alpha7nAChR, inhibition of p38 or JNK restored Abeta-induced levels of NMDAR1, NMDAR2A, NMDAR2B, GluR1, GluR2 and PSD95 in Abeta-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 alpha7nAChR mRNA levels in the hippocampus. Our results indicated that inhibition of p38 or JNK MAPKs could alleviate Abeta-induced spatial memory deficits through regulating activation of alpha7nAChR via recovering memory-related proteins. Moreover, p38, ERK and JNK MAPKs exert different functions in spatial and recognition memory.