Phosphatidylinositol-3-kinase activation blocks amyloid beta-induced neurotoxicity

Abstract

The phosphatidylinositol-3-kinase (P13-K) pathway has been suggested to play a pivotal role in neuronal survival. Although P13-K has been recently identified as a neuroprotectant, there are no reports regarding the effect of a direct P13-K activator on A beta-induced neurotoxicity. We investigated whether direct P13-K activation prevents A beta-induced neurotoxicity. To evaluate the effect of A beta on neuronal cells, we treated primary cultured cortical neurons with several doses of A beta for 72 h. To investigate the protective effect that P13-K activation has on A beta-induced neurotoxicity, cells were simultaneously treated with several doses of a P13-K activator for 72 h. An MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay, trypan blue staining, and DAPI staining showed that A beta decreased neuronal cell viability in a concentration-dependent manner and also that P13-K activation effectively prevented A beta-induced neuronal cell death. A beta significantly decreased survival signals, including phosphorylated Akt, glycogen synthase kinase-3 beta, and heat shock transcription factor-1. A beta also increased death signals, such as phosphorylated tau (pThr231) and activated caspase-3. Treatment with a P13-K activator restored the survival signals and inhibited the death signals. These results suggest that the neurotoxic effect of A beta can be partially prevented by P13-K activation.