One of the pathological hallmarks of Alzheimer's disease (AD) is deposition of extracellular amyloid-beta (Abeta) peptide, which is generated from the cleavage of amyloid precursor protein (APP). Accumulation of Abeta is thought to associate with the progressive neuronal death observed in AD. However, the precise signaling mechanisms underlying the action of Abeta in AD pathophysiology are not completely understood. Here, we report the involvement of the transcription factor signal transducer and activator of transcription 3 (STAT3) in mediating Abeta-induced neuronal death. We find that tyrosine phosphorylation of STAT3 is elevated in the cortex and hippocampus of APP/PS1 transgenic mice. Treatment of cultured rat neurons with Abeta or intrahippocampal injection of mice with Abeta both induces tyrosine phosphorylation of STAT3 in neurons. Importantly, reduction of either the expression or activation of STAT3 markedly attenuates Abeta-induced neuronal apoptosis, suggesting that STAT3 activation contributes to neuronal death after Abeta exposure. We further identify Tyk2 as the tyrosine kinase that acts upstream of STAT3, as Abeta-induced activation of STAT3 and caspase-3-dependent neuronal death can be inhibited in tyk2(-/-) neurons. Finally, increased tyrosine phosphorylation of STAT3 is also observed in postmortem brains of AD patients. Our observations collectively reveal a novel role of STAT3 in Abeta-induced neuronal death and suggest the potential involvement of Tyk2/STAT3 signaling in AD pathophysiology.