Activation of α7 nicotinic acetylcholine receptor alleviates Aβ1-42-induced neurotoxicity via downregulation of p38 and JNK MAPK signaling pathways

Amyloid beta peptide 1-42 (A beta(1-42)) could induce cognitive deficits through oxidative stress, inflammation, and neuron death in Alzheimer's disease (AD). MAPK pathways have been thought to mediate A beta(1-42)-induced neuroinflammation responses, neuron death and cognitive decline in AD. The alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR) exerts a neuroprotective effect. However, whether a7nAChR alleviates A beta(1-42) -induced neurotoxicity through MAPKs (p38, ERK, JNK) in vivo remains unclear. In our study, memory was assessed in C57BL/6 mice using a Y-maze test. Cell death was assessed by Nissl and Hoechst staining and Bax, Bcl-2, Caspase 3, and Cytochrome C levels using Western blotting. Oxidative stress was assayed by superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) levels. Inflammation was examined with GFAP and Iba1 using immunohistochemistry. The A beta degrading enzymes insulin degrading enzyme (IDE) and neprilysin (NEP) were tested using Western blotting. We found that activating alpha 7nAChR or inhibiting p38 or JNK pathway alleviated A beta(1-42)-induced cognitive deficits and neuron loss and death by reducing oxidative stress. In addition, activating alpha 7nAChR or inhibiting p38 or JNK pathway also reduced inflammation, which was observed as reduced GFAP and Iba1 levels with different effects on AD degrading enzymes. Finally, we found that the activation of alpha 7nAChR led to the downregulation of pp38 and pJNK levels. Conversely, the inhibition of p38 or JNK resulted in the upregulation of alpha 7nAChR levels in the hippocampus and cortex. Our data indicate that the activation of alpha 7nAChR alleviates A beta(1-42)-induced neurotoxicity, and this protective effect might act through the down regulation of p38 and JNK MAPKs.