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Activation of &agr;7 nicotinic acetylcholine receptor alleviates A&bgr;1‐42‐induced neurotoxicity via downregulation of p38 and JNK MAPK signaling pathways

Kewei Chang,Hang-Fan Zong,Kaige Ma,Wanying Zhai,Weina Yang,Xiao-dan Hu,Jie-hua Xu,Xinlin Chen,Shengfeng Ji,Yi-hua Qian

Published 2018 in Neurochemistry International

ABSTRACT

&NA; Amyloid &bgr; peptide 1–42 (A&bgr;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&bgr;1‐42‐induced neuroinflammation responses, neuron death and cognitive decline in AD. The &agr;7 nicotinic acetylcholine receptor (&agr;7nAChR) exerts a neuroprotective effect. However, whether &agr;7nAChR alleviates A&bgr;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&bgr; degrading enzymes insulin degrading enzyme (IDE) and neprilysin (NEP) were tested using Western blotting. We found that activating &agr;7nAChR or inhibiting p38 or JNK pathway alleviated A&bgr;1‐42‐induced cognitive deficits and neuron loss and death by reducing oxidative stress. In addition, activating &agr;7nAChR or inhibiting p38 or JNK pathway also reduced inflammation, which was observed as reduced GFAP and Iba1 levels with different effects on A&bgr; degrading enzymes. Finally, we found that the activation of &agr;7nAChR led to the downregulation of pp38 and pJNK levels. Conversely, the inhibition of p38 or JNK resulted in the upregulation of &agr;7nAChR levels in the hippocampus and cortex. Our data indicate that the activation of &agr;7nAChR alleviates A&bgr;1‐42‐induced neurotoxicity, and this protective effect might act through the downregulation of p38 and JNK MAPKs. HighlightsActivation of &agr;7nAChR mitigates A&bgr;‐induced cognitive deficits via p38 and JNK MAPKs.Activation of &agr;7nAChR prevents cell death, oxidative stress and neuroinflammation.Activation of &agr;7nAChR reduces the levels of insulin degrading enzyme and neprilysin.

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