Proteomic analysis of postsynaptic density in Alzheimer's disease.
Proteomic analysis of postsynaptic density in Alzheimer's disease.
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阿尔茨海默病突触后密度的蛋白质组学分析。
DOI：
10.1016/j.cca.2013.03.016
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Peng,Junmin
中科院分区：
文献类型：
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作者：
Zhou,Jianying;Jones,DrewR;Duong,DucM;Levey,AllanI;Lah,JamesJ;Peng,Junmin
突触功能丧失是阿尔茨海默病（AD）发展的关键机制。突触后密度（PSD）的结构改变和可塑性丧失可能与发病机制有关。然而，引发突触功能障碍的潜在分子事件仍然难以捉摸。我们报告了一项定量蛋白质组学分析，从可能和确定的AD病例的人类死后脑组织中提取PSD。方法采用发现法和靶向质谱法进行分析，并进行生物重复。在发现研究中，我们比较了psd富集组分中的数百种蛋白质，发现25种蛋白质在AD中受到差异调节。结果有趣的是，在确定的阿尔茨海默病病例中，大多数蛋白质的变化比可能的阿尔茨海默病病例更大。在靶向分析中，我们测量了9个核心PSD蛋白的水平，发现只有IRSp53在AD中高度下调。通过免疫印迹法对7例对照和8例AD病例进一步验证了所选蛋白（即internexin和IRSp53）的改变。结论这些结果扩大了我们对AD如何影响PSD组成的理解，并提示了AD发病机制的新假设。
BACKGROUNDThe loss of synaptic function is a pivotal mechanism in the development of Alzheimer's Disease (AD). Structural changes and loss of plasticity in the postsynaptic density (PSD) may contribute to the pathogenesis. However, the underlying molecular events triggering synaptic dysfunction remain elusive. We report a quantitative proteomic analysis of the PSD from human postmortem brain tissues of possible and definite AD cases.METHODSThe analysis used both discovery and targeted mass spectrometry approaches and was repeated with biological replicates. During the discovery study, we compared several hundred proteins in the PSD-enriched fractions and found that 25 proteins were differentially regulated in AD.RESULTSInterestingly, the majority of these protein changes were larger in definite AD cases than in possible AD cases. In the targeted analysis, we measured the level of 9 core PSD proteins and found that only IRSp53 was highly down-regulated in AD. The alteration of selected proteins (i.e. internexin and IRSp53) was further validated by immunoblotting against 7 control and 8 AD cases.CONCLUSIONSThese results expand our understanding of how AD impacts PSD composition, and hints at new hypotheses for AD pathogenesis.