Involvement of α7nAChR in the Protective Effects of Genistein Against β-Amyloid-Induced Oxidative Stress in Neurons via a PI3K/Akt/Nrf2 Pathway-Related Mechanism

• DOI: 10.1007/s10571-020-01009-8
• Publication Date: 2020-11-19T22:22:09Z
• Authors: Jianbin Guo; Guoqing Yang; Yuqing He; Huiming Xu; Hong Fan; Jing An; Lingling Zhang; Rui Zhang; Guihua Cao; Dingjun Hao; Hao Yang
• Keywords: Neurons; 0301 basic medicine; Amyloid beta-Peptides; Kelch-Like ECH-Associated Protein 1; alpha7 Nicotinic Acetylcholine Receptor; NF-E2-Related Factor 2; Genistein; Hippocampus; Models, Biological; Peptide Fragments; 3. Good health; Rats, Sprague-Dawley; Oxidative Stress; 03 medical and health sciences; Neuroprotective Agents; Necroptosis; Animals; Phosphatidylinositol 3-Kinase; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction

Abnormal excessive production and deposition of β-amyloid (Aβ) peptides in selectively susceptible brain regions are thought to be a key pathogenic mechanism underlying Alzheimer's disease (AD), resulting in memory deficits and cognitive impairment. Genistein is a phytoestrogen with great promise for counteracting diverse Aβ-induced insults, including oxidative stress and mitochondrial dysfunction. However, the exact molecular mechanism or mechanisms underlying the neuroprotective effects of genistein against Aβ-induced insults are largely uncharacterized. To further elucidate the possible mechanism(s) underlying these protective effects, we investigated the neuroprotective effects of genistein against Aβ-induced oxidative stress mediated by orchestrating α7 nicotinic acetylcholine receptor (α7nAChR) signaling in rat primary hippocampal neurons. Genistein significantly increased cell viability, reduced the number of apoptotic cells, decreased accumulation of reactive oxygen species (ROS), decreased contents of malondialdehyde (MDA) and lactate dehydrogenase (LDH), upregulated BCL-2 expression, and suppressed Caspase-3 activity occurring after treatment with 25 μM Aβ25-35. Simultaneously, genistein markedly inhibited the decreases in α7nAChR mRNA and protein expression in cells treated with Aβ25-35. In addition, α7nAChR signaling was intimately involved in the genistein-mediated activation of phosphatidylinositol 3-kinase (PI3K)/Akt and Nrf2/keap1 signaling. Thus, α7nAChR activity together with the PI3K/Akt/Nrf2 signaling cascade likely orchestrates the molecular mechanism underlying the neuroprotective effects of genistein against Aβ-induced oxidative injury.