Integrated multi-omics analysis revealed the molecular networks and potential targets of cellular senescence in Alzheimer's disease.

Yudi Xu, Shutong Liu, Zhaokai Zhou, Hongzhuo Qin, Yuyuan Zhang, Ge Zhang, Hongxuan Ma, Xinwei Han, Huimin Liu, Zaoqu Liu

Department of Neurology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Dong Road, ErQi District, Zhengzhou, Henan 450052, China.Department of Neurology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Dong Road, ErQi District, Zhengzhou, Henan 450052, China. · pubmed

Paper

Abstract

Cellular senescence (CS) is a hallmark of Alzheimer's disease (AD). However, the mechanisms through which CS contributes to AD pathogenesis remain poorly understood. We found that CS level in AD was higher compared with the healthy control group. Transcriptome-based differential expression analysis identified 113 CS-related genes in blood and 410 in brain tissue as potential candidate genes involved in AD. To further explore the causal role of these genes, an integrative mendelian randomization analysis was conducted, combining AD genome-wide association study summary statistics with expression quantitative trait loci (eQTL) and DNA methylation quantitative trait loci (mQTL) data from blood samples, which identified five putative AD-causal genes (CENPW, EXOSC9, HSPB11, SLC44A2, and SLFN12) and 18 corresponding DNA methylation probes. Additionally, integrative analysis between eQTLs and mQTLs from blood uncovered two genes and 12 corresponding regulatory elements involved in AD. Furthermore, two genes (CDKN2B and ITGAV) were prioritized as putative causal genes in brain tissue and were validated through in vitro experiments. The multi-omics integration study revealed the potential role and underlying biological mechanisms of CS driven by genetic predisposition in AD. This study contributed to fundamental understanding of CS in AD pathogenesis and facilitated the identification of potential therapeutic targets for AD prevention and treatment.

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Research summary

The paper investigates the role of cellular senescence in Alzheimer's disease, which is indeed an age-related condition. It explores the molecular mechanisms underlying senescence and its contribution to AD pathogenesis, potentially addressing root causes of aging-related diseases. However, while the findings are solid and contribute to the understanding of the biological mechanisms involved, the impact is limited as it primarily focuses on a specific disease rather than broader aging processes or lifespan extension strategies.

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