Tyk2/STAT3 Signaling Mediates β-Amyloid-Induced Neuronal Cell Death: Implications in Alzheimer's Disease

One of the pathological hallmarks of Alzheimer's disease (AD) is deposition of extracellular amyloid-beta(A beta) peptide, which is generated from the cleavage of amyloid precursor protein (APP). Accumulation of A beta is thought to associate with the progressive neuronal death observed in AD. However, the precise signaling mechanisms underlying the action of A beta 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 A beta -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 A beta or intrahippocampal injection of mice with A beta both induces tyrosine phosphorylation of STAT3 in neurons. Importantly, reduction of either the expression or activation of STAT3 markedly attenuates A beta-induced neuronal apoptosis, suggesting that STAT3 activation contributes to neuronal death after A beta exposure. We further identify Tyk2 as the tyrosine kinase that acts upstream of STAT3, as A beta-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 A beta -induced neuronal death and suggest the potential involvement of Tyk2/STAT3 signaling in AD pathophysiology.