Involvement Of Alpha 7nachr In The Protective Effects Of Genistein Against Beta-Amyloid-Induced Oxidative Stress In Neurons Via A Pi3k/Akt/Nrf2 Pathway-Related Mechanism

Abnormal excessive production and deposition of beta-amyloid (A beta) 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 A beta-induced insults, including oxidative stress and mitochondrial dysfunction. However, the exact molecular mechanism or mechanisms underlying the neuroprotective effects of genistein against A beta-induced insults are largely uncharacterized. To further elucidate the possible mechanism(s) underlying these protective effects, we investigated the neuroprotective effects of genistein against A beta-induced oxidative stress mediated by orchestrating alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR) 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 mu M A beta 25-35. Simultaneously, genistein markedly inhibited the decreases in alpha 7nAChR mRNA and protein expression in cells treated with A beta 25-35. In addition, alpha 7nAChR signaling was intimately involved in the genistein-mediated activation of phosphatidylinositol 3-kinase (PI3K)/Akt and Nrf2/keap1 signaling. Thus, alpha 7nAChR activity together with the PI3K/Akt/Nrf2 signaling cascade likely orchestrates the molecular mechanism underlying the neuroprotective effects of genistein against A beta-induced oxidative injury.