Mitochondrial dysfunction gene expression, DNA methylation, and inflammatory cytokines interaction activate Alzheimer’s disease: a multi-omics Mendelian randomization study

Autor: Xiao-Xue Zhang, Meng Wei, He-Ran Wang, Ya-Zhuo Hu, Hong-Mei Sun, Jian-Jun Jia
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Journal of Translational Medicine, Vol 22, Iss 1, Pp 1-11 (2024)
Druh dokumentu: article
ISSN: 1479-5876
DOI: 10.1186/s12967-024-05680-z
Popis: Abstract Background Mitochondrial dysfunction (MD) is increasingly recognized as a key pathophysiological contributor in Alzheimer disease (AD). As differential MD genes expression may serve as either a causative factor or a consequence in AD, and expression of these genes could be influenced by epigenetic modifications or interact with inflammatory cytokines, hence, the precise role of MD in AD remains uncertain. Methods Meta-analysis of brain transcriptome datasets was conducted to pinpoint differentially expressed genes (DEGs) associated with MD in AD. We utilized three-step SMR to analyze the AD genome-wide association study summaries with expression quantitative trait loci (eQTLs) and DNA methylation QTLs from the blood and brain tissues, respectively. Through SMR and colocalization analysis, we further explored the interactions between brain eQTLs and inflammatory cytokines. Results Five datasets were meta-analyzed to prioritize 825 DEGs in AD from 1339 MD-related genes. Among these, seven genes from blood samples such as NDUFS8 and SPG7 and thirty-two genes from brain tissue including CLU and MAPT were identified as candidate AD-causal MD genes and regulated by methylation level. Furthermore, we revealed 13 MD gene expression-inflammatory pathway pairs involving LDLR, ACE and PTPMT1 along with interleukin-17C, interleukin-18 and hepatocyte growth factor. Conclusions This study highlighted that the AD-causal MD genes could be regulated by epigenetic changes and interact with inflammatory cytokines, providing evidence for AD prevention and intervention.
Databáze: Directory of Open Access Journals
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