The α-secretase-derived form of the amyloid precursor protein (sAPPα), which is released from neurons in an activity-dependent manner, has been shown to promote long-term survival of hippocampal and cortical neurons in culture and can protect those neurons against excitotoxic and ischemic injury in culture and in vivo. The signal transduction pathway(s) activated by sAPPα has not been established. We now report that sAPPα activates the phosphatidylinositol-3-kinase (PI₃K)–Akt kinase signaling pathway in cultured hippocampal neurons. sAPPα also stimulates phosphorylation of p42 (ERK1) and p44 (ERK2) mitogen-activated protein (MAP) kinases by a PI₃K-independent pathway. Treatment of neurons with sAPPα protects them against death induced by trophic factor deprivation and exposure to glutamate, and these survival-promoting effects of sAPPα are abolished or attenuated when either PI₃K or p42/p44 MAP kinases are selectively blocked. Exposure of neurons to sAPPα resulted in a decrease in the level of IκBβ and an increase in NF-κB DNA binding activity, both of which were blocked by wortmannin, suggesting that the transcription factor NF-κB may be a downstream target of the PI₃K–Akt pathway that may play a role in the cell survival-promoting action of sAPPα. These findings suggest that the PI₃K–Akt pathway and p42/p44 MAP kinases mediate responses of neurons to sAPPα in physiological and pathological settings, with implications for synaptic plasticity and the pathogenesis of Alzheimer's disease.