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Objective Humanin (HN) is a 24-amino acid bioactive peptide abolishing neuronal cell death induced by various familial AD-related genes and amyloid-β (Aβ).[Gly14]-humanin (HNG), a derivative of HN, has been reported to have much stronger neuroprotective effects than natural HN in vitro and in vivo.Our previous studies also indicated that HNG could protect against Aβ-induced impairments of hippocampal LTP and spatial learning and memory.However, the underlying molecular mechanisms by which HNG plays neuroprotective roles remain largely unknown.In view of the important roles of STATs and Caspase-3 in normal cellular activities or pathological apoptosis, the present study is designed to explore the influence of HNG on the gene expression of STAT3 and Caspase-3 in the AD related animal model.Methods SD rats were pretreated by intrahippocampal injection of Aβ31-35, HNG, and genistein (a specific inhibitor of tyrosine kinases).The expressions of STAT3 and Caspase-3 mRNA in the hippocampus were analyzed in real-time RT-PCR.Results (1) Compared with control, the level of Caspase-3 mRNA, in 5 nmol Aβ31-35 alone group, significantly increased, while STAT3 mRNA expression showed an obvious decrease.(2) 2 nmol HNG alone injection up-regulated STAT3 mRNA and down-regulated Caspase-3 mRNA.(3) In co-injection of HNG plus Aβ 31-35 group, the expression of Caspase-3 mRNA was markedly reduced and the level of STAT3 mRNA was increased compared with Aβ31-35 alone group.(4) After pretreatment with Genistein, the neuroprotective effect of HNG was significantly reduced in co-application of Genistein, HNG and Aβ 31-35 group.Conclusion (1) The Aβ-induced impairments of hippocmpal synaptic plasticity and animal cognitive behavior may be involved in the activation of Caspase-3-dependent intrinsic apoptotic pathways, as well as the suppression of STAT3mRNA expression.(2) The neuroprotective effects of HNG against Aβ neurotoxicity might be mediated by activating tyrosine kinase and STAT3 transcription factor, and blocking Caspase-3-dependent intrinsic apoptotic pathways.