Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly. Increasing evidence has shown that P-amyloid protein (A beta) production is the key pathological cause of AD. 7-(4Hydroxy-3-methoxypheny1)-1-pheny1-4E-hepten-3-one (AO-2), a natural diarylheptanoid, is previously found to have activities in neuronal differentiation and neurite outgrowth, and its analogue shows protective effects against All. In this study, we further investigated the function of AO-2 toward A beta induced injuries in PC12 cells and hippocampal neurons. Pretreatment of PC12 cells with AO-2 restored cell viability in a concentration-dependent manner against A beta-induced neurotoxicity. Moreover, the A beta stimulated apoptosis and caspase-3 activation were markedly inhibited by AO-2. We found that AO-2 prevented the downregulation of PI3K-Akt-mTOR signaling after A beta damage, and blockade of either PI3K or mTOR activity led to the failure of AO-2 on caspase-3 inhibition. We further showed that AO-2 was protective against two devastating effects of A beta, increased reactive oxygen species (ROS) production and dendrite injury, and this protection was also dependent on PI3K and mTOR activities. Taken together, this study showed that AO-2 acts against A beta-induced damages in PC12 cells and hippocampal neurons through PI3K-mTOR pathways, thus providing a new neuroprotective compound which may shed light on drug development of AD. (C) 2017 Elsevier Inc. All rights reserved.