闫鹏;乔娴;刘金玲;孙圣刚;郑瑾;

• 1:华中科技大学同济医学院附属协和医院神经内科

摘要(Abstract)：

目的:探讨YC-1针对Aβ寡聚体(ADDLs)毒性的保护作用及其相关机制。方法:原代培养小鼠皮质神经元及星形胶质细胞混合培养体系,应用不同浓度ADDLs(500 nmol/L、1μmol/L、2μmol/L、5μmol/L、10μmol/L、20μmol/L)干预以模拟体外AD模型,应用YC-1对此模型进行干预,以CCK-8法检测细胞活力,Western blot检测NICD及缺氧诱导因子-1α(HIF-1α)水平,采用real-time PCR检测Caspase-3 mRNA水平。结果:浓度≥2μmol/L的ADDLs干预明显降低混合培养体系细胞活力水平,并呈现浓度依赖性(P<0.01)。10μmol/L ADDLs持续干预4 h显著降低细胞活力(P<0.01),YC-1可明显拮抗这种毒性作用(P<0.01)。10μmol/L ADDLs持续干预4 h明显上调NICD及HIF-1α水平(P<0.01),YC-1可拮抗这种提高(P<0.05或0.01)。10μmol/L ADDLs干预4 h显著提高Caspase-3的mRNA水平(P<0.01),YC-1可显著抑制这种上调(P<0.05)。结论:ADDLs表现出对原代培养小鼠皮质神经元及星形胶质细胞混合培养体系的毒性作用,YC-1可发挥保护作用。

关键词(KeyWords)： YC-1;Aβ寡聚体;保护作用;NICD;缺氧诱导因子-1α

Abstract:

Keywords:

基金项目(Foundation): 国家自然科学基金青年基金(No.81301085)

作者(Author): 闫鹏;乔娴;刘金玲;孙圣刚;郑瑾;

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DOI:

参考文献(References)：

• [1]Cheng IH,Scearce-Levie K,Legleiter J,et al.Accelerating amyloid-βfibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse models[J].J Biol Chem,2007,282:23818-23828.
• [2]Hashmi S,Al-Salam S.Hypoxia-inducible factor-1 alpha in the heart:a double agent?[J].Cardiol Rev,2012,20:268-273.
• [3]Soucek T,Cumming R,Dargusch R,et al.The regulation of glucose metabolism by HIF-1mediates a neuroprotective response to amyloid beta peptide[J].Neuron,2003,39:43-56.
• [4]Schubert D,Soucek T,Blouw B.The induction of HIF‐1 reduces astrocyte activation by amyloid beta peptide[J].Eur J Neurosci,2009,29:1323-1334.
• [5]Du R,Sun W,Xia L,et al.Hypoxia-induced down-regulation of microRNA-34a promotes EMT by targeting the Notch signaling pathway in tubular epithelial cells[J].PloS one,2012,7:e30771.
• [6]Gao W,Sweeney C,Connolly M,et al.Notch-1 mediates hypoxia-induced angiogenesis in rheumatoid arthritis[J].Arthritis Rheumatism,2012,64:2104-2113.
• [7]Tsui L,Fong TH,Wang IJ.YC-1 targeting of hypoxia-inducible factor-1αreduces RGC-5 cell viability and inhibits cell proliferation[J].Mol Vis,2012,18:1594-1603.
• [8]Zhou Y,Klein WL.AβOligomers-induced toxicity is attenuated in cells cultured with NbActiv4?medium[J].Neurotox Res,2012,22:335-344.
• [9]Prangkio P,Yusko EC,Sept D,et al.Multivariate analyses of amyloid-beta oligomer populations indicate a connection between pore formation and cytotoxicity[J].PloS one,2012,7:e47261.
• [10]Ables JL,Breunig JJ,Eisch AJ,et al.Not(ch)just development:Notch signalling in the adult brain[J].Nat Rev Neurosci,2011,12:269-283.
• [11]Avramovich-Tirosh Y,Bar-Am O,Amit T,et al.Up-regulation of hypoxia-inducible factor(HIF)-1 and HIF-target genes in cortical neurons by the novel multifunctional iron chelator anti-Alzheimer drug,M30[J].Curr Alzheimer Res,2010,7:300-306.
• [12]Li L,Zhang X,Yang D,et al.Hypoxia increases Aβgeneration by alteringβ-andγ-cleavage of APP[J].Neurobiol Aging,2009,30:1091-1098.