Alzheimer's disease (AD) is a neurodegenerative disorder partly induced by dysregulation of different brain regions. Prefrontal cortex (PFC) dysregulation has been reported to associate with mental symptoms such as delusion, apathy, and depression in AD patients. However, the internal mechanisms have not yet been well-understood. This study aims to identify the potential therapeutic target genes and related pathways in PFC of AD. First, differential expression analyses were performed on transcriptome microarray of PFC between AD specimens and non-AD controls. Second, protein-protein interaction networks were constructed based on the identified differentially expressed genes to explore candidate therapeutic target genes. Finally, these candidate genes were validated through biological experiments. The enrichment analyses showed that the differentially expressed genes were significantly enriched in protein functions and pathways related to AD. Furthermore, the top ten hub genes in the protein-protein interaction network (ELAVL1, CUL3, MAPK6, FBXW11, YWHAE, YWHAZ, GRB2, CLTC, YWHAQ, and PDHA1) were proved to be directly or indirectly related to AD. Besides, six genes (PDHA1, CLTC, YWHAE, MAPK6, YWHAZ, and GRB2) of which were validated to significantly altered in AD mice by biological experiments. Importantly, the most significantly changed gene, PDHA1, was proposed for the first time that may be serve as a target gene in AD treatment. In summary, several genes and pathways that play critical roles in PFC of AD patients have been uncovered, which will provide novel insights on molecular targets for treatment and diagnostic biomarkers of AD.

中文翻译：

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阿尔茨海默氏病前额叶皮层关键调控基因和途径的鉴定。

阿尔茨海默氏病（AD）是一种神经退行性疾病，部分由不同大脑区域的失调引起。据报道，前额叶皮质（PFC）失调与AD患者的精神症状有关，例如妄想，冷漠和抑郁。但是，内部机制尚未被很好地理解。本研究旨在确定AD PFC中潜在的治疗靶基因和相关途径。首先，在AD标本和非AD对照之间的PFC转录组微阵列上进行差异表达分析。其次，基于鉴定的差异表达基因构建蛋白质-蛋白质相互作用网络，以探索候选治疗靶基因。最后，通过生物学实验验证了这些候选基因。富集分析表明差异表达的基因在与AD相关的蛋白质功能和途径中显着富集。此外，事实证明，蛋白质-蛋白质相互作用网络中的前十个中心基因（ELAVL1，CUL3，MAPK6，FBXW11，YWHAE，YWHAZ，GRB2，CLTC，YWHAQ和PDHA1）直接或间接与AD相关。此外，通过生物学实验证实其中六个基因（PDHA1，CLTC，YWHAE，MAPK6，YWHAZ和GRB2）在AD小鼠中显着改变。重要的是，首次提出了变化最大的基因PDHA1，该基因可作为AD治疗中的靶基因。总之，已经发现了在AD患者的PFC中起关键作用的几种基因和途径，这将为治疗和诊断AD的生物分子靶标提供新颖的见解。