An integrative genome-wide transcriptome reveals that candesartan is neuroprotective and a candidate therapeutic for Alzheimer's disease.
An integrative genome-wide transcriptome reveals that candesartan is neuroprotective and a candidate therapeutic for Alzheimer's disease.
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DOI：
10.1186/s13195-015-0167-5
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发表时间：
2016-01-28
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影响因子：
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通讯作者：
Saavedra JM
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作者：
Elkahloun AG;Hafko R;Saavedra JM
阿尔茨海默病是最常见的年龄相关性痴呆，目前没有治疗。为了确定早期治疗干预的可能靶点，我们重点研究了谷氨酸兴奋毒性（一种主要的早期致病因素）和坎地沙坦（一种血管紧张素受体阻滞剂）在细胞培养和阿尔茨海默病啮齿动物模型中的神经保护作用。该研究的总体目标是确定原代神经元培养中药物作用的基因分析是否与阿尔茨海默病中基因表达的改变相关，从而提供有益治疗效果的进一步临床前证据。原代神经元培养物用神经保护浓度的坎地沙坦处理，然后用兴奋毒性谷氨酸量处理。我们进行了全基因组表达谱分析和数据评估的独创性途径分析和基因集富集分析，与两个独立的发表的数据集的基因表达的变化进行了比较，通过对阿尔茨海默病患者死后海马的微阵列分析。脑血管内皮细胞或神经元中的优先表达通过与通过激光捕获显微切割从人皮质分离的这些细胞中的已发表基因表达进行比较来分析。坎地沙坦阻止了我们培养物中数百个基因的谷氨酸上调或下调。免疫抑制通路分析和基因集富集分析显示，炎症、心血管疾病和糖尿病信号转导通路以及β淀粉样蛋白代谢是谷氨酸兴奋毒性神经元反应的主要组成部分。进一步的分析表明，谷氨酸诱导的数百个基因表达的变化，通过坎地沙坦正常化，与阿尔茨海默病患者海马中观察到的类似变化相关。通过激光捕获显微切割获得的神经元和脑血管内皮细胞的基因分析显示，谷氨酸上调和下调的基因分别优先在内皮细胞和神经元中表达。我们的数据可能被解释为坎地沙坦的直接神经保护作用的证据超出了其对血压的影响，揭示了常见的和新的疾病机制，可能是在体外基因改变这里报道和谷氨酸诱导的细胞损伤阿尔茨海默病。我们的观察结果通过阿尔茨海默病损伤的早期分子机制为坎地沙坦神经保护提供了新的证据，支持在疾病早期阶段的对照临床研究中测试该化合物。本文的在线版本（doi：10.1186/s13195-015-0167-5）包含补充材料，可供授权用户使用。
Alzheimer’s disease is the most frequent age-related dementia, and is currently without treatment. To identify possible targets for early therapeutic intervention we focused on glutamate excitotoxicity, a major early pathogenic factor, and the effects of candesartan, an angiotensin receptor blocker of neuroprotective efficacy in cell cultures and rodent models of Alzheimer’s disease. The overall goal of the study was to determine whether gene analysis of drug effects in a primary neuronal culture correlate with alterations in gene expression in Alzheimer’s disease, thus providing further preclinical evidence of beneficial therapeutic effects. Primary neuronal cultures were treated with candesartan at neuroprotective concentrations followed by excitotoxic glutamate amounts. We performed genome-wide expression profile analysis and data evaluation by ingenuity pathway analysis and gene set enrichment analysis, compared with alterations in gene expression from two independent published datasets identified by microarray analysis of postmortem hippocampus from Alzheimer’s disease patients. Preferential expression in cerebrovascular endothelial cells or neurons was analyzed by comparison to published gene expression in these cells isolated from human cortex by laser capture microdissection. Candesartan prevented glutamate upregulation or downregulation of several hundred genes in our cultures. Ingenuity pathway analysis and gene set enrichment analysis revealed that inflammation, cardiovascular disease and diabetes signal transduction pathways and amyloid β metabolism were major components of the neuronal response to glutamate excitotoxicity. Further analysis showed associations of glutamate-induced changes in the expression of several hundred genes, normalized by candesartan, with similar alterations observed in hippocampus from Alzheimer’s disease patients. Gene analysis of neurons and cerebrovascular endothelial cells obtained by laser capture microdissection revealed that genes up- and downregulated by glutamate were preferentially expressed in endothelial cells and neurons, respectively. Our data may be interpreted as evidence of direct candesartan neuroprotection beyond its effects on blood pressure, revealing common and novel disease mechanisms that may underlie the in vitro gene alterations reported here and glutamate-induced cell injury in Alzheimer’s disease. Our observations provide novel evidence for candesartan neuroprotection through early molecular mechanisms of injury in Alzheimer’s disease, supporting testing this compound in controlled clinical studies in the early stages of the illness. The online version of this article (doi:10.1186/s13195-015-0167-5) contains supplementary material, which is available to authorized users.