Yeojin Kim, You Jin Nam, Sunwoo Yoon, Young Joon Cho, Ho Min Song, Seongmin Kim, Donghyuk Shin, Jin Young Noh, Sun Min Lee, So Young Moon, Eun-Joo Kim, Soo Hyun Cho, Byeong C Kim, Seong Hye Choi, Sang Won Seo, Jin Wook Choi, Young-Sil An, Bumhee Park, Young Joon Park, Hee Young Kang, Hyun Goo Woo, Yong Hyuk Cho, Sunhwa Hong, Sang Joon Son, Sang-Rae Lee, Chang Hyung Hong, Hyun Woong Roh
{"title":"阿尔茨海默病内质网应激的转录景观和生物标志物发现：一项使用患者来源的真皮成纤维细胞的离体研究","authors":"Yeojin Kim, You Jin Nam, Sunwoo Yoon, Young Joon Cho, Ho Min Song, Seongmin Kim, Donghyuk Shin, Jin Young Noh, Sun Min Lee, So Young Moon, Eun-Joo Kim, Soo Hyun Cho, Byeong C Kim, Seong Hye Choi, Sang Won Seo, Jin Wook Choi, Young-Sil An, Bumhee Park, Young Joon Park, Hee Young Kang, Hyun Goo Woo, Yong Hyuk Cho, Sunhwa Hong, Sang Joon Son, Sang-Rae Lee, Chang Hyung Hong, Hyun Woong Roh","doi":"10.30773/pi.2025.0101","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":21164,"journal":{"name":"Psychiatry Investigation","volume":"22 6","pages":"699-713"},"PeriodicalIF":1.8000,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Transcriptional Landscape and Biomarker Discovery for Endoplasmic Reticulum Stress in Alzheimer's Disease: An Ex Vivo Study Using Patients-Derived Dermal Fibroblasts.\",\"authors\":\"Yeojin Kim, You Jin Nam, Sunwoo Yoon, Young Joon Cho, Ho Min Song, Seongmin Kim, Donghyuk Shin, Jin Young Noh, Sun Min Lee, So Young Moon, Eun-Joo Kim, Soo Hyun Cho, Byeong C Kim, Seong Hye Choi, Sang Won Seo, Jin Wook Choi, Young-Sil An, Bumhee Park, Young Joon Park, Hee Young Kang, Hyun Goo Woo, Yong Hyuk Cho, Sunhwa Hong, Sang Joon Son, Sang-Rae Lee, Chang Hyung Hong, Hyun Woong Roh\",\"doi\":\"10.30773/pi.2025.0101\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>\",\"PeriodicalId\":21164,\"journal\":{\"name\":\"Psychiatry Investigation\",\"volume\":\"22 6\",\"pages\":\"699-713\"},\"PeriodicalIF\":1.8000,\"publicationDate\":\"2025-06-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Psychiatry Investigation\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.30773/pi.2025.0101\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/6/16 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"PSYCHIATRY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Psychiatry Investigation","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.30773/pi.2025.0101","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/6/16 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"PSYCHIATRY","Score":null,"Total":0}
Transcriptional Landscape and Biomarker Discovery for Endoplasmic Reticulum Stress in Alzheimer's Disease: An Ex Vivo Study Using Patients-Derived Dermal Fibroblasts.
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.
期刊介绍：
The Psychiatry Investigation is published on the 25th day of every month in English by the Korean Neuropsychiatric Association (KNPA). The Journal covers the whole range of psychiatry and neuroscience. Both basic and clinical contributions are encouraged from all disciplines and research areas relevant to the pathophysiology and management of neuropsychiatric disorders and symptoms, as well as researches related to cross cultural psychiatry and ethnic issues in psychiatry. The Journal publishes editorials, review articles, original articles, brief reports, viewpoints and correspondences. All research articles are peer reviewed. Contributions are accepted for publication on the condition that their substance has not been published or submitted for publication elsewhere. Authors submitting papers to the Journal (serially or otherwise) with a common theme or using data derived from the same sample (or a subset thereof) must send details of all relevant previous publications and simultaneous submissions. The Journal is not responsible for statements made by contributors. Material in the Journal does not necessarily reflect the views of the Editor or of the KNPA. Manuscripts accepted for publication are copy-edited to improve readability and to ensure conformity with house style.
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