Phosphatidylinositol-3-kinase activation blocks amyloid beta-induced neurotoxicity.
The phosphatidylinositol-3-kinase (PI3-K) pathway has been suggested to play a pivotal role in neuronal survival. Although PI3-K has been recently identified as a neuroprotectant, there are no reports regarding the effect of a direct PI3-K activator on Abeta-induced neurotoxicity. We investigated whether direct PI3-K activation prevents Abeta-induced neurotoxicity. To evaluate the effect of Abeta on neuronal cells, we treated primary cultured cortical neurons with several doses of Abeta for 72 h. To investigate the protective effect that PI3-K activation has on Abeta-induced neurotoxicity, cells were simultaneously treated with several doses of a PI3-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 Abeta decreased neuronal cell viability in a concentration-dependent manner and also that PI3-K activation effectively prevented Abeta-induced neuronal cell death. Abeta significantly decreased survival signals, including phosphorylated Akt, glycogen synthase kinase-3beta, and heat shock transcription factor-1. Abeta also increased death signals, such as phosphorylated tau (pThr231) and activated caspase-3. Treatment with a PI3-K activator restored the survival signals and inhibited the death signals. These results suggest that the neurotoxic effect of Abeta can be partially prevented by PI3-K activation.
Lee
Kyu-Yong
KY
Department of Neurology, College of Medicine, Hanyang University, Seoul, Republic of Korea.
Koh
Seong-Ho
SH
Noh
Min Young
MY
Kim
Seung Hyun
SH
Lee
Young Joo
YJ
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005609:Free Radicals / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000201:enzymology / Q000209:etiology / Q000378:metabolism; D010446:Peptide Fragments / Q000633:toxicity*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D005609:Free Radicals; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C075222:amyloid beta-protein (1-42)