Dissecting Mitochondrial Mechanisms of Alzheimer’s Disease Using Gene Dependency Network and Its Implications for Discovering Nutrients Combatting the Disease

Article type: Research Article

Authors: Xu, Xuan^{a; b} | Wang, Hui^{c; d} | Zhang, Qing-Ye^a | Meng, Xiang-Yu^{a; e} | Li, Xin-Xing^a | Zhang, Hong-Yu^{a; *; 1}

Affiliations: [a] Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan, China | [b] College of Life Sciences, Anhui Medical University, Hefei, China | [c] Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA | [d] Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA | [e] Health Science Center, Hubei Minzu University, Enshi, China

Correspondence: [*] Correspondence to: Hong-Yu Zhang, Huazhong Agricultural University, No. 1 Shizishan Street, Hongshan District, Wuhan, Hubei 430070, China. Tel.: +86 27 8728 0877; E-mail: [email protected].

Note: [1] Statistical Analysis conducted by Xuan Xu, PhD, and Hui Wang, PhD, Huazhong Agricultural University and University of Pennsylvania.

Abstract: Background: Alzheimer’s disease (AD) is the leading cause of dementia, with its prevalence increasing as the global population ages. AD is a multifactorial and intricate neurodegenerative disease with pathological changes varying from person to person. Because the mechanism of AD is highly controversial, effective treatments remain a distant prospect. Currently, one of the most promising hypotheses posits mitochondrial dysfunction as an early event in AD diagnosis and a potential therapeutic target. Objective: Here, we adopted a systems medicine strategy to explore the mitochondria-related mechanisms of AD. Then, its implications for discovering nutrients combatting the disease were demonstrated. Methods: We employed conditional mutual information (CMI) to construct AD gene dependency networks. Furthermore, the GeneRank algorithm was applied to prioritize the gene importance of AD patients and identify potential anti-AD nutrients targeting crucial genes. Results: The results suggested that two highly interconnected networks of mitochondrial ribosomal proteins (MRPs) play an important role in the regulation of AD pathology. The close association between mitochondrial ribosome dysfunction and AD was identified. Additionally, we proposed seven nutrients with potential preventive and ameliorative effects on AD, five of which have been supported by experimental reports. Conclusions: Our study explored the important regulatory role of MRP genes in AD, which has significant implications for AD prevention and treatment.

Keywords: Alzheimer’s disease, biomarker, drug discovery, gene dependency network, mitochondria, nutrients

DOI: 10.3233/JAD-230366

Journal: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1709-1722, 2023