Proteomics of plasma-derived extracellular vesicles reveals S100A8 as a novel biomarker for Alzheimer's disease: A preliminary study

IF 2.8 2区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of proteomics Pub Date : 2024-08-17 DOI:10.1016/j.jprot.2024.105279

Yidan Zhang , Yuan Zhao , Jian Zhang , Ya Gao , Xuan Gao , Shuyue Li , Cui Chang , Guofeng Yang

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引用次数: 0

Abstract

Extracellular vesicles (EVs) act as mediators for intercellular transfer of Aβ and tau proteins, promoting the propagation of these pathological misfolded proteins throughout the brain in Alzheimer's disease (AD). Levels of blood exosomal Aβ₄₂, total Tau (t-Tau) and phosphorylated Tau (p-Tau) had a high correlation with their concentrations in cerebrospinal fluid (CSF), demonstrating that exosomal biomarkers have equal contribution as those in CSF for the diagnosis of AD. We aimed to comprehensively characterize the proteome of plasma-derived EVs to identify differentially expressed proteins (DEPs) and pathways in AD. Tandem mass tag (TMT) labeled quantitative proteomics was applied to analyze plasma-derived EV proteins in 9 AD patients and 9 healthy controls. 335 proteins were quantified, and 12 DEPs were identified including seven upregulated proteins and five down-regulated proteins. Oligomerized Aβ_1–42 induced SH-SY5Y cell damage model was built to mimic the pathological changes of AD, and small interfering RNA (siRNA) against S100A8 was used to knock down S100A8 expression. Results displayed S100A8 was down regulated in plasma-derived EVs from AD patients, while enriched in EVs derived from Aβ_1–42-induced SH-SY5Y cells. Furthermore, Aβ_1–42-induced SH-SY5Y cells treated with S100A8 siRNA showed decreased Aβ levels in cell lysate and EVs, especially in EVs.

Significance

The investigation aimed to comprehensively characterize the proteome of plasma-derived EVs to identify DEPs and potential biomarker of AD. S100A8 was found down regulated in plasma-derived EVs from AD patients using TMT labeled quantitative proteomics. The diagnostic value of S100A8 was also confirmed using receiver operating characteristic curve (ROC) analysis. Furthermore, Aβ_1–42-induced SH-SY5Y cells treated with S100A8 siRNA showed decreased Aβ levels in cell lysate and EVs, especially in EVs. The preliminary findings suggest that suppression of S100A8 expression inhibits Aβ aggregation both in cell lysate and EVs from Aβ_1–42-induced SH-SY5Y cells, and S100A8 more likely regulates Aβ aggregation via EVs. Therefore, plasma-derived EV S100A8 might be a potential biomarker of AD. Manipulation of S100A8 expression may be a novel therapeutic strategy in the treatment of AD.

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血浆源性细胞外囊泡的蛋白质组学发现 S100A8 是阿尔茨海默病的新型生物标记物：初步研究

细胞外囊泡（EVs）是Aβ和tau蛋白细胞间转移的媒介，促进了阿尔茨海默病（AD）中这些病理折叠错误蛋白在整个大脑中的传播。血液外泌体Aβ42、总Tau（t-Tau）和磷酸化Tau（p-Tau）的水平与它们在脑脊液（CSF）中的浓度有很高的相关性，这表明外泌体生物标志物与脑脊液中的生物标志物对诊断AD有同等的贡献。我们的目的是全面描述血浆衍生EVs的蛋白质组，以确定AD中的差异表达蛋白（DEPs）和通路。我们应用串联质量标签（TMT）标记的定量蛋白质组学分析了9名CE患者和9名健康对照者的血浆衍生EV蛋白。共定量分析了335种蛋白质，并鉴定出12种DEPs，包括7种上调蛋白质和5种下调蛋白质。建立了寡聚Aβ1-42诱导的SH-SY5Y细胞损伤模型来模拟AD的病理变化，并使用针对S100A8的小干扰RNA（siRNA）来敲除S100A8的表达。结果显示，S100A8在AD患者血浆衍生的EV中被下调，而在Aβ1-42诱导的SH-SY5Y细胞衍生的EV中富集。此外，Aβ1-42-诱导的SH-SY5Y细胞经S100A8 siRNA处理后，细胞裂解物和EVs中的Aβ水平下降，尤其是EVs中。意义：这项研究旨在全面描述血浆衍生EVs的蛋白质组，以确定DEPs和AD的潜在生物标记物。利用 TMT 标记的定量蛋白质组学发现，S100A8 在 AD 患者的血浆衍生 EV 中被下调。接收者操作特征曲线（ROC）分析也证实了S100A8的诊断价值。此外，Aβ1-42-诱导的SH-SY5Y细胞经S100A8 siRNA处理后，细胞裂解物和EVs中的Aβ水平下降，尤其是EVs。初步研究结果表明，抑制 S100A8 的表达可抑制 Aβ1-42- 诱导的 SH-SY5Y 细胞的细胞裂解物和 EVs 中 Aβ 的聚集，S100A8 更有可能通过 EVs 调节 Aβ 的聚集。因此，血浆衍生的EV S100A8可能是AD的潜在生物标志物。操纵S100A8的表达可能是治疗AD的一种新型治疗策略。

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来源期刊

Journal of proteomics 生物-生化研究方法

CiteScore

7.10

自引率

3.00%

发文量

227

审稿时长

73 days

期刊介绍： Journal of Proteomics is aimed at protein scientists and analytical chemists in the field of proteomics, biomarker discovery, protein analytics, plant proteomics, microbial and animal proteomics, human studies, tissue imaging by mass spectrometry, non-conventional and non-model organism proteomics, and protein bioinformatics. The journal welcomes papers in new and upcoming areas such as metabolomics, genomics, systems biology, toxicogenomics, pharmacoproteomics. Journal of Proteomics unifies both fundamental scientists and clinicians, and includes translational research. Suggestions for reviews, webinars and thematic issues are welcome.