Immune-Related Gene Expression in Neurodegeneration and

神经退行性变和免疫相关基因表达

• 批准号: 7325436
• 负责人: DENNIS D. TAUB
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7325436
• 关键词: Immune; Related; Gene; Expression; Neurodegeneration

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.

阿尔茨海默病发病和进展的分子机制？疾病（AD）还没有得到很好的理解。微阵列技术被用来隔离疾病特异性的基因表达的变化，通过采样跨下顶叶的患者患有AD或非AD相关的痴呆症和非痴呆症的控制，主要集中在了解炎症如何可能在AD发病机制中发挥作用。随后在一组扩大的样品上验证了数据。基因本体分析显示，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相关，其次是炎症和免疫信号相关基因。通路分析还暗示了趋化因子及其受体，更具体地说是CXCR 4和CCR 3在AD发病机制中的作用。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。蛋白质印迹分析表明，增加激活的PKC，下游介质的趋化因子受体信号，在大多数AD患者相比，对照组。此外，与对照受试者相比，AD患者中与淀粉样蛋白β积累和清除相关的一组非常特定的基因发生了显著改变。在该神经元基因数据集中最显著下调的基因是内皮素转化酶2（ECE 2），其是一种涉及β-淀粉样蛋白清除的酶，尽管ECE表达的丧失尚未在人AD组织中得到证实。在AD样品的微阵列数据集中，ECE 2表达显著下调，这些数据随后通过真实的时间PCR和Western印迹分析证实。总之，这些发现开辟了新的研究途径和可能的治疗策略，针对炎症和淀粉样蛋白清除AD患者。