阿尔茨海默病内质网应激的转录图谱与生物标志物发现：一项使用患者来源的皮肤成纤维细胞的体外研究

Transcriptional Landscape and Biomarker Discovery for Endoplasmic Reticulum Stress in Alzheimer's Disease: An Ex Vivo Study Using Patients-Derived Dermal Fibroblasts.

作者信息

Kim Yeojin, Nam You Jin, Yoon Sunwoo, Cho Young Joon, Song Ho Min, Kim Seongmin, Shin Donghyuk, Noh Jin Young, Lee Sun Min, Moon So Young, Kim Eun-Joo, Cho Soo Hyun, Kim Byeong C, Choi Seong Hye, Seo Sang Won, Choi Jin Wook, An Young-Sil, Park Bumhee, Park Young Joon, Kang Hee Young, Woo Hyun Goo, Cho Yong Hyuk, Hong Sunhwa, Son Sang Joon, Lee Sang-Rae, Hong Chang Hyung, Roh Hyun Woong

机构信息

Department of Biomedical Sciences, Graduate School of Ajou University, Suwon, Republic of Korea.

Department of Psychiatry, Ajou University School of Medicine, Suwon, Republic of Korea.

出版信息

Psychiatry Investig. 2025 Jun;22(6):699-713. doi: 10.30773/pi.2025.0101. Epub 2025 Jun 16.

DOI:10.30773/pi.2025.0101

PMID:40566894

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12198892/

Abstract

OBJECTIVE

Numerous studies have identified various risk factors associated with Alzheimer's disease (AD). However, the experimental limitations of disease modeling make it challenging to directly interpret their effects. These limitations include constraints of postmortem samples, animal experiments, and challenges associated with brain tissue studies. Ex vivo experiments effectively address these issues by enabling patient-specific identification and highlighting potential biomarkers. This study aimed to characterize the transcriptional profile of fibroblasts derived from patients with AD in response to endoplasmic reticulum (ER) stress and propose potential biomarkers.

METHODS

We utilized an ex vivo platform to identify genes differentially responsive to ER stress. The transcriptional feature of fibroblasts in both healthy controls (n=22) and patients with AD (n=20) was analyzed using bulk RNA sequencing. The cytotoxicity of the selected target gene was evaluated through knockdown experiments.

RESULTS

A total of 468 differentially expressed genes (DEGs) were identified. Gene ontology and pathway enrichment analysis revealed that 210 DEGs, which were less responsive in AD, are involved in lipid-related terms and pathways. By narrowing down AD-related genes, we identified 49 highly reliable AD-associated genes. The most significant gene, DCTN2, exhibited a fold change that positively correlated with cognitive function and negatively correlated with blood-based biomarkers (pTau217, amyloid beta 42/40 ratio), aligning with the amyloid/Tau/neurodegeneration research criteria for AD. Additionally, the knockdown of DCTN2 in glial cell lines resulted in increased cell toxicity and apoptosis.

CONCLUSION

Identifying differentially responsive genes in ex vivo experiments not only provides insights into the pathology of AD but also offers potential biomarkers for disease diagnosis.

摘要

目的

众多研究已确定了与阿尔茨海默病（AD）相关的各种风险因素。然而，疾病建模的实验局限性使得直接解读其影响具有挑战性。这些局限性包括尸检样本、动物实验的限制以及与脑组织研究相关的挑战。体外实验通过实现患者特异性识别并突出潜在生物标志物，有效地解决了这些问题。本研究旨在表征源自AD患者的成纤维细胞对内质网（ER）应激的转录谱，并提出潜在的生物标志物。

方法

我们利用一个体外平台来识别对内质网应激有不同反应的基因。使用批量RNA测序分析了健康对照者（n = 22）和AD患者（n = 20）中成纤维细胞的转录特征。通过敲低实验评估所选靶基因的细胞毒性。

结果

共鉴定出468个差异表达基因（DEG）。基因本体和通路富集分析表明，在AD中反应较弱的210个DEG参与了脂质相关的术语和通路。通过缩小与AD相关的基因范围，我们确定了49个高度可靠的AD相关基因。最显著的基因DCTN２，其倍数变化与认知功能呈正相关，与血液生物标志物（pTau217，淀粉样β蛋白42/40比值）呈负相关，符合AD的淀粉样蛋白/ Tau /神经退行性变研究标准。此外，在胶质细胞系中敲低DCTN2导致细胞毒性和凋亡增加。