The pathogenesis of Alzheimer disease (AD) involves the complex interaction between genetic and environmental factors affecting multiple cellular pathways. Recent advances in systems biology provide a system-level understanding of AD by elucidating the genome-wide molecular interactions. By using KeyMolnet, a bioinformatics tool for analyzing molecular interactions on the curated knowledgebase, we characterized molecular network of 2,883 all stages of AD-related genes (ADGs) and 559 incipient AD-related genes (IADGs) identified by global gene expression profiling of the hippocampal CA1 region of AD brains in terms of significant clinical and pathological correlations (Blalock et al., Proc Natl Acad Sci USA 101: 2173-2178, 2004). By the common upstream search, KeyMolnet identified cAMP-response element-binding protein (CREB) as the principal transcription factor exhibiting the most significant relevance to molecular networks of both ADGs and IADGs. The CREB-regulated transcriptional network included upregulated and downregulated sets of ADGs and IADGs, suggesting an involvement of generalized deregulation of the CREB signaling pathway in the pathophysiology of AD, beginning at the early stage of the disease. To verify the in silico observations in vivo, we conducted immunohistochemical studies of 11 AD and 13 age-matched control brains by using anti-phoshorylated CREB (pCREB) antibody. An abnormal accumulation of pCREB imunoreactivity was identified in granules of granulovacuolar degeneration (GVD) in the hippocampal neurons of AD brains. These observations suggest that aberrant CREB-mediated gene regulation serves as a molecular biomarker of AD-related pathological processes, and support the hypothesis that sequestration of pCREB in GVD granules is in part responsible for deregulation of CREB-mediated gene expression in AD hippocampus.

中文翻译：

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分子网络分析表明阿尔茨海默病海马中存在异常的 CREB ​​介导的基因调控。

阿尔茨海默病 (AD) 的发病机制涉及影响多个细胞通路的遗传和环境因素之间的复杂相互作用。系统生物学的最新进展通过阐明全基因组分子相互作用提供了对 AD 的系统级理解。通过使用 KeyMolnet，一种用于分析精选知识库上分子相互作用的生物信息学工具，我们表征了 2,883 个 AD 相关基因 (ADG) 的所有阶段和 559 个初始 AD 相关基因 (IADG) 的分子网络，这些基因通过全球基因表达谱确定AD 大脑的海马 CA1 区在显着的临床和病理相关性方面（Blalock 等，Proc Natl Acad Sci USA 101：2173-2178，2004）。通过共同的上游搜索，KeyMolnet 将 cAMP 反应元件结合蛋白 (CREB) 鉴定为与 ADG 和 IADG 的分子网络最显着相关的主要转录因子。CREB ​​调控的转录网络包括 ADGs 和 IADGs 的上调和下调集，这表明 CREB ​​信号通路在 AD 的病理生理学中的普遍失调涉及从疾病的早期阶段开始。为了验证体内计算机观察，我们通过使用抗磷酸化 CREB ​​(pCREB) 抗体对 11 个 AD 和 13 个年龄匹配的对照大脑进行了免疫组织化学研究。在 AD 大脑海马神经元的颗粒空泡变性 (GVD) 颗粒中发现了 pCREB ​​免疫反应性的异常积累。这些观察结果表明，异常 CREB ​​介导的基因调控可作为 AD 相关病理过程的分子生物标志物，并支持 GVD 颗粒中 pCREB ​​的隔离部分导致 AD 海马中 CREB ​​介导的基因表达失调的假设。