Immune-Related Gene Expression in Neurodegeneration and

阿尔茨海默病-S病(AD)发生和发展的分子机制尚不清楚。利用微阵列技术，通过采集AD患者或非AD相关痴呆患者和非痴呆对照患者的下顶叶样本，分离疾病特异性基因表达的变化，主要重点是了解炎症可能如何在AD发病机制中发挥作用。随后，在一组扩大的样本上验证了数据。基因本体论分析表明，差异表达最多的基因与神经系统发育和功能以及神经系统疾病有关，其次是与炎症和免疫信号有关的基因。通路分析还表明趋化因子及其受体，更具体地说是CXCR4和CCR3，在AD的发病机制中发挥了作用。免疫组织化学分析显示，这些趋化因子受体在AD患者中显著上调。Western印迹分析显示，与对照组相比，大多数AD患者中趋化因子受体信号的下游中介PKC的激活增加。此外，与对照组相比，AD患者中与淀粉样β蛋白积累和清除相关的一组非常特殊的基因被发现发生了显著的变化。在这个神经元基因数据集中，下调最显著的基因是内皮素转换酶2(ECE2)，这是一种与β-淀粉样蛋白清除有关的酶，尽管在人类AD组织中尚未证实ECE2的表达缺失。在AD样本的微阵列数据集中，ECE2的表达显著下调，这些数据随后被实时荧光聚合酶链式反应和蛋白质印迹分析证实。总之，这些发现为研究AD患者的炎症和淀粉样蛋白清除开辟了新的途径和可能的治疗策略。

The molecular mechanisms underlying the onset and progression of Alzheimer?s disease (AD) are not well understood. Microarray technology was utilized to isolate disease-specific changes in gene expression by sampling across inferior parietal lobes of patients suffering from AD or non-AD-associated dementia and non-demented controls, with a primary focus on understanding how inflammation might play a role in AD pathogenesis. Data was subsequently validated on an expanded set of samples. Gene ontology analysis revealed that the most differentially expressed genes related to nervous system development and function and neurological disease, followed closely by genes involved in inflammation and immunological signaling. Pathway analysis also implicated a role for chemokines and their receptors, more specifically CXCR4 and CCR3, in AD pathogenesis. Immunohistological analysis revealed that these chemokine receptors are significantly upregulated in AD patients. Western blot analysis demonstrated an increased activation of PKC, a downstream mediator of chemokine receptor signaling, in the majority of AD patients compared to control subjects. Moreover, a very specific cohort of genes related to amyloid beta accumulation and clearance were found to be significantly altered in AD versus control subjects. The most significantly down regulated gene in this neuronal gene data set was the endothelin converting enzyme 2 (ECE2), an enzyme implicated in beta-amyloid clearance although loss of ECE expression has yet to be demonstrated in human AD tissues. ECE2 expression was significantly down-regulated in the microarray dataset of AD samples and these data were subsequently confirmed by real time PCR and Western blot analysis. Together, these findings open up new avenues of investigation and possible therapeutic strategies targeting inflammation and amyloid clearance in AD patients.