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Identification of Key Regulatory Genes and Pathways in Prefrontal Cortex of Alzheimer’s Disease

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Abstract

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.

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Acknowledgements

We would like to thank Dr. Shen for his constructive suggestions on our statistical analysis. This paper has been accepted by the 4th CCF Bioinformatics Conference (CBC2019).

Funding

This work was partially supported by the National Natural Science Foundation of China (No. 61873156), and the Project of Natural Science Foundation of Shanghai (No. 17ZR1409900).

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Author notes

  1. Fuzhang Yang and Xin Diao are joint first authors.

Authors and Affiliations

  1. School of Computer Engineering and Science, Shanghai University, Shanghai, China

    Fuzhang Yang, Xin Diao, Jiamin Sun & Jiang Xie

  2. Laboratory of Molecular Neural Biology, School of Life Sciences, Shanghai University, Shanghai, China

    Fushuai Wang & Quanwei Wang

  3. Laboratory on Naturopathy, College of Physical Education, Shanghai University, Shanghai, China

    Yan Zhou

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  1. Fuzhang Yang
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  2. Xin Diao
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Correspondence to Jiang Xie.

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Yang, F., Diao, X., Wang, F. et al. Identification of Key Regulatory Genes and Pathways in Prefrontal Cortex of Alzheimer’s Disease. Interdiscip Sci Comput Life Sci 12, 90–98 (2020). https://doi.org/10.1007/s12539-019-00353-8

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