Neurotoxicity Induced by Okadaic Acid in the Human Neuroblastoma SH-SY5Y Line Can Be Differentially Prevented by α7 and β2*Nicotinic Stimulation

A good model of neuronal death that reproduces the characteristic tau (tau) hyperphosphorylation of Alzheimers disease is the use of okadaic acid (OA). The aim of this study was to determine the contribution of alpha 7 and beta 2* nicotinic acetylcholine receptor (nAChR) subtypes to neuroprotection against OA in the SH-SY5Y cell line by using the selective alpha 7 and beta 2* nAChR agonists PNU 282987 and 5-Iodo-A85380, respectively. The results of this study show that both alpha 7 and beta 2* nAChR can afford neuroprotection against OA-induced neurotoxicity. Protection mediated by alpha 7 nAChRs was independent of Ca2+ and involved the intracellular signaling pathway Janus Kinase-2/Phosphatidylinositol-3-kinase/Akt. When Ca2+ entry was promoted through the alpha 7 nAChR by using the alpha 7-selective positive allosteric modulator PNU 120596, protection was lost. By contrast, protection mediated by beta 2* nAChRs was Ca2+ dependent and implicated the signaling pathways PI3K/Akt and extracellular regulated kinase 1/2. Both alpha 7 and beta 2* nAChR activation converged on downregulation of GSK-3 beta and reduction of tau phosphorylation in cells undergoing cell death induced by OA. Therefore, targeting nAChR could offer a strategy for reducing neurodegeneration secondary to hyperphosphorylation of protein tau.