微体古生物学报

γ-分泌酶的Aph1亚基多样性与阿尔茨海默病相关

 

[2][3][8][参考文献]BellacosaA,TestaJR,StaalSP,et a1.A retroviral onco— gene,Akt,encoding a serine—threonine kinase contai— ning anSH2一like region[J].Science,1991,254(5029):274—277.张琳,李东野,夏勇,等.阳离子脂质体转染Akt基因对缺血性心脏病细胞凋亡的影响[J].江苏医药,2009,35(4):440—442.Marin—GarciaJ,GoldenthalMJ.Mitochondria play a critical role in cardioproteetion[J].JCardFail,2004,10(1):55—66.李东野,闫艳,朱红,等.HIF—l饯基因对心肌梗死后心肌细胞凋亡和心功能影响的实验研究[J].中国病理生理杂志,2008,24(2):275—278.AsaBG,RobertaAG.Heart mitochondria:gates of life and death[J].CardiovascRes,2008,77(2):334—343.ShanmuganathanS,HausenloyDJ,DuehenMR, et a1.Mitochondrial permeability transition pore as a target for cardioprotection in the human heart[J].AmJPhysiolHeartCircPhysiol,2005,289(1):H237一H242.JavadovS,KarmazynM.Mitoehondrial permeability tran— sition pore opening as an endpoint to initiate cell death and as a putative target for cardioprotection[J].CellPhysiolBiochem,2007,20(1—4):1—22.CromptonM,NazarethW,YafeiN.Inhibition of anoxia—induced injury in heart myocytes by cyclosporinA[J].[9][10]·85·MolCellCardiol,1991,23(12):1351—1354.NakagawaT,ShimizuS,WatanabeT,et a1.CyclophilinD dependent mitoehondrial permeability transition regu— lates some necrotic but not apoptotic cell death[J].Na— ture,2005,434(7033):652—658.MatsuiT,TaoJ,delMonteF,et a1.Akt activation pre— serves cardiac function and prevents injury after transient cardiac ischemia in vivo[J].Circulation,2001,104(3):330—335.CarolynJ,Mullonkal.Akt in ischemia and reperfusion[J].JInvestSurg,2007,20(3):195—203.KoricanacG,MilosavljevicT,StojiljkovicM,et a1.Im— pact of estradiol on insulin signaling in the rat heart[J].CellBiochemFunct,2009,27(2):102—110.SheuML,HoFM,YangRS,et a1.High glucose induces human endothelial cell apoptosis through a phosphoinosit— ide3一kinase regulated cyclooxygenase一2 pathway[J].ArterioselerThrombVascBiol,2005,25(3):539—545.MatsuiT,LiL,delMonteF,et a1.Adenoviral gene transfer of activated phosphatidylinositol3’一 kinase andAkt inhibits apoptosis of hypoxic cardiomyoeytes in vitro[J].Circulation,1999,100(23):2373—2379.GnecchiM,HeH,LiangOD,et a1.Paracrine action accounts for marked protection of ischemic heart byAkt—modified mesenchymal stem cells[J].NatMed,2005,11(4):367—368.Y一分泌酶的Aphl亚基多样性与阿尔茨海默病相关1一分泌酶复合体(吖一secretase complex)在阿尔茨海默病(Alzheimer’s disease,AD)和癌症发病机制中均起重要作用。1一分泌酶的活性由早老素(presenilin,PS)、Aphl、Pen2和Nicastrin蛋白(NCT)组成的多蛋白复合体来介导,主要影响前体淀粉样蛋白(amyloid precursor protein,APP)的裂解,释放p一淀粉样蛋白(amyloid—B,A13),形成AD特征性的淀粉样斑块。1一分泌酶同样可以裂解Notch蛋白、N一钙黏着蛋白和其他重要的信号分子。目前临床使用的对AD作用有效的抑制剂大都根据控制膜内Notch或其它必需蛋白质水解的1一分泌酶复合物而设计,有较多的副作用。科学家发现不同组织中的叮一分泌酶复合物包含不同类型的早老素和Aphl蛋白亚基,呈现生物化学和生理学性质的多样性。在实验性小鼠AD模型中,Aphl蛋白通过影响原位上有催化作用的PSl亚基的构型调节1一分泌酶复合体的水解活性。特异性抑制AphlB复合物的活性能显著改善小鼠AD模型的临床表现而无Notch相关副作用。AphlBC。一小鼠AD模型中可以观察到大脑中淀粉样病理变化明显降低,学习记忆的行为学指标也有较大改善。由于AphlB复合物决定了人类脑中全部1一分泌酶的活性,因此,设计针对AphlB的1一分泌酶复合体的药物在AD治疗过程中可能获得高效低毒的结果。同时,也提示针对1一分泌酶的治疗应用于其他领域例如包括造血系统和肿瘤的可能性。Science,2009,324(5927):639—642(别曼)1IJ1J1l,1J1JU抡BM埒 rL rL rL rL rLH随∞口