I型干扰素信号转导活性受损与临床前阿尔茨海默病患者外周血转录组有关。

Impaired type I interferon signaling activity implicated in the peripheral blood transcriptome of preclinical Alzheimer's disease.

机构信息

Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai 200433, China.

Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai 200433, China; MOE Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200433, China; Zhangjiang Fudan International Innovation Center, Shanghai 200433, China.

出版信息

EBioMedicine. 2022 Aug;82:104175. doi: 10.1016/j.ebiom.2022.104175. Epub 2022 Jul 18.

DOI:10.1016/j.ebiom.2022.104175

PMID:35863293

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9304603/

Abstract

BACKGROUND

Subjective or objective subtle cognitive decline (SCD) is considered the preclinical manifestation of Alzheimer's disease (AD), which is a potentially crucial window for preventing or delaying the progression of the disease.

METHODS

To explore the potential mechanism of disease progression and identify relevant biomarkers, we comprehensively assessed the peripheral blood transcriptomic alterations in SCD, covering lncRNA, mRNA, and miRNA.

FINDINGS

Dysregulated protein-coding mRNA at both gene and isoform levels implicated impairment in the type I interferon signaling pathway in SCD. Specifically, this pathway was regulated by the transcription factor STAT1 and ncRNAs NRIR and has-miR-146a-5p. The miRNA-mRNA-lncRNA co-expression network revealed hub genes for the interferon module. Individuals with lower interferon signaling activity and lower expression of a hub gene STAT1 exhibited a higher conversion rate to mild cognitive impairment (MCI).

INTERPRETATION

Our findings illustrated the down-regulation of interferon signaling activity would potentially increase the risk of disease progression and thus serve as a pre-disease biomarker.

FUNDING

This work was partly supported by National Key R&D Program of China (2020YFA0712403), National Natural Science Foundation of China (61932008), Shanghai Municipal Science and Technology Major Project (2018SHZDZX01), the 111 Project (No. B18015) of China, Greater Bay Area Institute of Precision Medicine (Guangzhou) (Grand No. IPM21C008), Natural Science Foundation of Shanghai (21ZR1403200), and Shanghai Center for Brain Science and Brain-Inspired Technology.

摘要

背景

主观或客观的细微认知衰退（SCD）被认为是阿尔茨海默病（AD）的临床前表现，这是预防或延缓疾病进展的潜在关键窗口。

方法

为了探索疾病进展的潜在机制并确定相关生物标志物，我们全面评估了 SCD 外周血转录组的改变，涵盖了 lncRNA、mRNA 和 miRNA。

发现

在基因和异构体水平上失调的蛋白编码 mRNA 表明 SCD 中 I 型干扰素信号通路受损。具体而言，该途径受转录因子 STAT1 和 ncRNAs NRIR 和 has-miR-146a-5p 的调节。miRNA-mRNA-lncRNA 共表达网络揭示了干扰素模块的枢纽基因。干扰素信号活性较低和枢纽基因 STAT1 表达较低的个体向轻度认知障碍（MCI）的转化率更高。

解释

我们的研究结果表明，干扰素信号活性的下调可能会增加疾病进展的风险，因此可以作为疾病前的生物标志物。

资助

本工作得到了中国国家重点研发计划（2020YFA0712403）、国家自然科学基金（61932008）、上海市重大科技专项（2018SHZDZX01）、中国 111 计划（No. B18015）、广州大湾区精准医学研究院（Grand No. IPM21C008）、上海市自然科学基金（21ZR1403200）和上海脑科学与类脑智能技术中心的部分支持。