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ORIGINAL RESEARCH article

Front. Aging Neurosci.
Sec. Alzheimer's Disease and Related Dementias
Volume 16 - 2024 | doi: 10.3389/fnagi.2024.1423725

Senescence-related genes and proteins in the development of Alzheimer's disease: evidence from transcriptomic and Mendelian randomization analysis

Provisionally accepted
Ying Liu Ying Liu Jiao Chen Jiao Chen *
  • Shengjing Hospital of China Medical University, Shenyang, China

The final, formatted version of the article will be published soon.

    Purpose: Alzheimer's disease (AD) is a common neurodegenerative disease, which can lead to cognitive impairment and dementia. Since AD is tightly associated with aging and cellular senescence, objective of this study was to investigate the association between senescence-related genes and proteins (SRGs and SRPs) and the development of AD. Design: The whole study was based on transcriptomic analysis of control and AD brain tissues and Mendelian randomization (MR) analysis. Methods: For transcriptomic analysis, GSE5281 dataset from GEO database contains the transcriptomic data of human brain tissues (n = 161) from control group and AD patients. The expression of SRGs in control and AD brain tissues were compared by Student's t test. For MR analysis, the instrumental single-nucleotide polymorphisms (SNPs) associated with 110 SRPs were filtered and selected from a large genome-wide association study (GWAS) for plasma proteome. The causality between plasma levels of SRPs and AD was explored using GWAS data of AD from Lambert et al. (17,008 cases and 37,154 controls) and further validated by using data from FinnGen consortium (6,489 patients and 170,489 controls). MR estimate was performed using the inversevariance weighted (IVW) method and the heterogeneity and pleiotropy of results were tested. Results: Transcriptomic analysis identified 36 up-regulated (including PLAUR) and 8 downregulated SRGs in AD brain tissues. In addition, the MR results at both discovery and validation stages supported the causality between plasma levels of PLAUR (IVW-P = 3.04E-2, odds ratio [OR] = 1.15), CD55 (IVW-P = 1.56E-3, OR = 0.86), and SERPINE2 (IVW-P = 2.74E-2, OR = 0.91) and the risk of AD. Conclusion: Our findings identified that PLAUR, as an SRG, may take part in the development of AD and found that high plasma levels of PLAUR was associated with increased risk of AD, indicating that this gene was a risk factor for this disease and providing the rationale of existing drugs or new preventative and therapeutic strategies.

    Keywords: Alzheimer's disease, senescence, Transcriptomic Analysis, Plasma proteome, Mendelian randomization

    Received: 26 Apr 2024; Accepted: 23 Jul 2024.

    Copyright: © 2024 Liu and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Jiao Chen, Shengjing Hospital of China Medical University, Shenyang, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.