DAPK1调控癫痫发作诱导的阿尔茨海默病样病变

DAPK1 regulates seizure-induced AD-like pathology

目的 探讨死亡相关蛋白激酶1 (death-associated protein kinase 1,DAPK1)对小鼠癫痫发作诱导阿尔茨海默病(Alzheimer's disease,AD)样病变的调控。方法 C57BL/6小鼠经腹腔注射25 mg·kg^(-1)海人藻酸(kainic acid,KA),建立颞叶癫痫(temporal lobe epilepsy,TLE)模型,对照小鼠注射等量生理盐水,检测小鼠海马体中淀粉样代谢通路中关键蛋白的表达,可溶性β淀粉样蛋白(amyloidβ-protein,Aβ)的分泌,tau的高度磷酸化及DAPK1通路的活化;WT小鼠和Dapk1 KO小鼠经腹腔注射KA,考察DAPK1对KA诱导的AD样病变的影响。结果TLE小鼠海马体中可溶性Aβ的分泌、淀粉样代谢通路中关键蛋白的表达、tau的磷酸化水平,以及DAPK1的表达和活性均高于对照小鼠。相比WT小鼠,Dapk1 KO小鼠海马体中KA诱导的Aβ的分泌和tau的磷酸化水平均明显下降。结论 TLE诱导了小鼠AD样病变,而DAPK1敲除可缓解小鼠脑老化的特征。

Aim To investigate the regulation of death-associated protein kinase 1(DAPK1)on seizure-induced Alzheimer’s disease(AD)-like pathology.Methods Two-month old C57BL/6 mice were given intraperitoneal injection of 25 mg·kg-1 kainic acid(KA)to establish a temporal lobe epilepsy(TLE)model,and control mice were injected with an equal amount of saline.The expression of key proteins in the amyloid metabolic pathway,the secretion of soluble amyloidβ-protein(Aβ),the high phosphorylation of tau,and the activation of DAPK1 pathway were detected in hippocampus of mice.WT mice and Dapk1 KO mice were given intraperitoneal injections of KA,then the effect of DAPK1 on seizure-induced AD-like pathology was examined.Results The secretion of soluble Aβ,the expression of key proteins in the amyloid metabolic pathway,the level of phosphorylation of tau,and the expression and activity of DAPK1 were higher in the hippocampus of TLE mice than in the control mice.Compared with WT mice,KA-induced Aβsecretion and tau phosphorylation were significantly reduced in hippocampus of Dapk1 KO mice.Conclusion TLE induces AD-like pathology in mice,and DAPK1 knockout alleviates symptoms of aging in mouse brain.