Del Barrio_2011_Toxicol.Sci_123_193

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 alpha7 and beta2* nicotinic acetylcholine receptor (nAChR) subtypes to neuroprotection against OA in the SH-SY5Y cell line by using the selective alpha7 and beta2* nAChR agonists PNU 282987 and 5-Iodo-A85380, respectively. The results of this study show that both alpha7 and beta2* nAChR can afford neuroprotection against OA-induced neurotoxicity. Protection mediated by alpha7 nAChRs was independent of Ca(2+) and involved the intracellular signaling pathway Janus Kinase-2/Phosphatidylinositol-3-kinase/Akt. When Ca(2+) entry was promoted through the alpha7 nAChR by using the alpha7-selective positive allosteric modulator PNU 120596, protection was lost. By contrast, protection mediated by beta2* nAChRs was Ca(2+) dependent and implicated the signaling pathways PI3K/Akt and extracellular regulated kinase 1/2. Both alpha7 and beta2* nAChR activation converged on downregulation of GSK-3beta 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.