A study exploring the effects of exercise on cuproptosis targets in Alzheimer's disease brains based on large-scale data.

IF 3.6 4区医学 Q1 MEDICINE, GENERAL & INTERNAL

Archives of Medical Science Pub Date : 2026-04-16 eCollection Date: 2026-01-01 DOI:10.5114/aoms/216654

Guang Yang, Qi Li

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引用次数: 0

Abstract

Introduction: Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by memory loss and cognitive decline. Epidemiological studies have linked sedentary behaviour to increased risk of chronic diseases, but the molecular mechanisms connecting prolonged inactivity to AD remain unclear. Copper dyshomeostasis and a newly defined form of copper-induced cell death - cuproptosis - have been implicated in neurodegeneration. This study investigates the role of cuproptosis-related genes in sedentary elderly individuals and AD patients to identify potential biomarkers and therapeutic targets.

Material and methods: Gene expression profiles from GEO datasets GSE110298 (hippocampus, sedentary AD vs. control) and GSE9103 (skeletal muscle, sedentary vs. active aging) were processed with the limma package (|log₂FC| ≥ 1, adj. p < 0.05). Differentially expressed genes (DEGs) were intersected with a curated cuproptosis gene list. KEGG and GO analyses identified enriched pathways. Protein-protein interaction (PPI) networks in Cytoscape highlighted hub genes. Key candidates were validated by quantitative PCR (qPCR) and Western blot in hippocampal and quadriceps tissues of exercise and sedentary mouse models.

Results: In GSE110298 and GSE9103, 2480 and 890 DEGs were identified, respectively, with 90 overlapping genes enriched in mitochondrial metabolism and neurodegeneration pathways. PPI analysis ranked DLD and DLAT as top hubs; these two remained after intersecting with the cuproptosis gene set. Both DLD and DLAT were significantly upregulated in hippocampi of sedentary AD subjects and in skeletal muscle of sedentary aging individuals. qPCR confirmed 1.6- to 2.8-fold mRNA increases for DLD and DLAT (p < 0.001), and Western blot showed 1.5- to 2.0-fold protein elevation (p < 0.05). Additional modulation of TXN and FDX1 was observed.

Conclusions: Our integrative analysis identifies DLD and DLAT as key cuproptosis markers dysregulated by sedentary behaviour in AD-relevant tissues. These findings implicate copper-driven cell death in linking prolonged inactivity to neurodegeneration, and highlight DLD/DLAT as promising biomarkers and therapeutic targets. Future work should expand cohort validation and dissect mechanistic roles via multi-omics and functional assays.

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一项基于大规模数据的研究，探索运动对阿尔茨海默病大脑中cuprotosis目标的影响。

阿尔茨海默病（AD）是一种以记忆丧失和认知能力下降为特征的进行性神经退行性疾病。流行病学研究已将久坐行为与慢性病风险增加联系起来，但将长期不活动与AD联系起来的分子机制尚不清楚。铜平衡失调和一种新定义的铜诱导细胞死亡形式-铜增生-与神经退行性变有关。本研究探讨了铜倾相关基因在久坐老年人和AD患者中的作用，以确定潜在的生物标志物和治疗靶点。材料和方法：GEO数据集GSE110298（海马，久坐性AD与对照组）和GSE9103（骨骼肌，久坐性AD与活动性衰老）的基因表达谱用limma软件包处理（|log2FC|≥1,adj. p < 0.05）。差异表达基因（DEGs）与精心设计的异位基因表相交。KEGG和GO分析发现了富集的通路。蛋白-蛋白相互作用（PPI）网络在Cytoscape突出中心基因。通过定量PCR （qPCR）和Western blot对运动和久坐小鼠海马和股四头肌组织进行验证。结果：在GSE110298和GSE9103中，分别鉴定出2480和890个deg，其中90个重叠基因富集于线粒体代谢和神经退行性途径。PPI分析将DLD和DLAT列为顶级枢纽；这两个基因在与铜突起基因集相交后仍然存在。久坐型AD受试者海马和久坐型衰老个体骨骼肌中的DLD和DLAT均显著上调。qPCR结果显示DLD和DLAT mRNA表达增加1.6 ~ 2.8倍（p < 0.001）， Western blot结果显示蛋白表达增加1.5 ~ 2.0倍（p < 0.05）。观察到TXN和FDX1的额外调制。结论：我们的综合分析确定了DLD和DLAT是ad相关组织中久坐行为失调的关键骨质增生标志物。这些发现暗示了铜驱动的细胞死亡与长期不活动与神经退行性变之间的联系，并强调DLD/DLAT是有希望的生物标志物和治疗靶点。未来的工作应该通过多组学和功能分析来扩大队列验证和剖析机制作用。

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来源期刊

Archives of Medical Science 医学-医学：内科

CiteScore

4.90

自引率

7.90%

发文量

139

审稿时长

1.7 months

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