Lovastatin protects human neurons against Aβ-induced toxicity and causes activation of β-catenin-TCF/LEF signaling

Alzheimer's disease (AD) is characterized by cognitive decline due to excess amyloid beta peptide (Aβ), neurofibrillary tangles, and neuronal loss. Aβ promotes neuronal apoptosis in AD by activating glycogen synthase kinase-3β (GSK-3β), leading to degradation of β-catenin and inactivation of Wnt signaling. β-Catenin interacts with the T-cell factor (TCF)/Lymphoid enhancer factor (LEF)-nuclear complex to mediate Wnt signaling and cell survival. Statins are associated with decreased prevalence of AD. Lovastatin has been shown to decrease the production of Aβ and to promote neuronal survival. The mechanisms of how statins promote neuronal survival are unclear. We propose that the neuroprotective effect of lovastatin may be due to inactivation of GSK-3β activity, resulting in induction of Wnt signaling. Here, we report that lovastatin prevented Aβ-induced apoptosis in human SK-NSH cells. This was accompanied by reduction in active GSK-3β, and increased nuclear translocation of β-catenin, TCF-3, and LEF-1. Lovastatin treatment induced an increase in TCF/LEF-chloramphenicol acetyl transferase (CAT) gene reporter activity. More importantly, β-catenin and TCF were required for the neuroprotective function of lovastatin. Our results suggest that lovastatin protects neuronal cells from Aβ-induced apoptosis and causes reduction in GSK-3β activity, resulting in activation of Wnt signaling.