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

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

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

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

Department of Neurology

Research output: Contribution to journal › Article › peer-review

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 theamyloid/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.

Original language	English
Pages (from-to)	699-713
Number of pages	15
Journal	Psychiatry Investigation
Volume	22
Issue number	6
DOIs	https://doi.org/10.30773/pi.2025.0101
State	Published - Jun 2025

Keywords

Alzheimer’s disease
Biomarker
Endoplasmic reticulum stress
Ex vivo study
Fibroblast

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Kim, Y., Nam, Y. J., Yoon, S., Cho, Y. J., Song, H. M., Kim, S., Shin, D., Noh, J. Y., Lee, S. M., Moon, S. Y., Kim, E. J., Cho, S. H., Kim, B. C., Choi, S. H., Seo, S. W., Choi, J. W., An, Y. S., Park, B., Park, Y. J., ... Roh, H. W. (2025). Transcriptional Landscape and Biomarker Discovery for Endoplasmic Reticulum Stress in Alzheimer’s Disease: An Ex Vivo Study Using Patients-Derived Dermal Fibroblasts. Psychiatry Investigation, 22(6), 699-713. https://doi.org/10.30773/pi.2025.0101

@article{bda473c3decf47f19e890ff458d38e51,

title = "Transcriptional Landscape and Biomarker Discovery for Endoplasmic Reticulum Stress in Alzheimer{\textquoteright}s Disease: An Ex Vivo Study Using Patients-Derived Dermal Fibroblasts",

abstract = "Objective Numerous studies have identified various risk factors associated with Alzheimer{\textquoteright}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 theamyloid/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.",

keywords = "Alzheimer{\textquoteright}s disease, Biomarker, Endoplasmic reticulum stress, Ex vivo study, Fibroblast",

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

note = "Publisher Copyright: {\textcopyright} 2025 Korean Neuropsychiatric Association.",

year = "2025",

month = jun,

doi = "10.30773/pi.2025.0101",

language = "English",

volume = "22",

pages = "699--713",

journal = "Psychiatry Investigation",

issn = "1738-3684",

publisher = "Korean Neuropsychiatric Association",

number = "6",

}

Kim, Y, Nam, YJ, Yoon, S, Cho, YJ, Song, HM, Kim, S, Shin, D, Noh, JY, Lee, SM, Moon, SY, Kim, EJ, Cho, SH, Kim, BC, Choi, SH, Seo, SW, Choi, JW, An, YS, Park, B, Park, YJ, Kang, HY, Woo, HG, Cho, YH, Hong, S, Son, SJ, Lee, SR, Hong, CH & Roh, HW 2025, 'Transcriptional Landscape and Biomarker Discovery for Endoplasmic Reticulum Stress in Alzheimer’s Disease: An Ex Vivo Study Using Patients-Derived Dermal Fibroblasts', Psychiatry Investigation, vol. 22, no. 6, pp. 699-713. https://doi.org/10.30773/pi.2025.0101

TY - JOUR

T1 - Transcriptional Landscape and Biomarker Discovery for Endoplasmic Reticulum Stress in Alzheimer’s Disease

T2 - An Ex Vivo Study Using Patients-Derived Dermal Fibroblasts

AU - Kim, Yeojin

AU - Nam, You Jin

AU - Yoon, Sunwoo

AU - Cho, Young Joon

AU - Song, Ho Min

AU - Kim, Seongmin

AU - Shin, Donghyuk

AU - Noh, Jin Young

AU - Lee, Sun Min

AU - Moon, So Young

AU - Kim, Eun Joo

AU - Cho, Soo Hyun

AU - Kim, Byeong C.

AU - Choi, Seong Hye

AU - Seo, Sang Won

AU - Choi, Jin Wook

AU - An, Young Sil

AU - Park, Bumhee

AU - Park, Young Joon

AU - Kang, Hee Young

AU - Woo, Hyun Goo

AU - Cho, Yong Hyuk

AU - Hong, Sunhwa

AU - Son, Sang Joon

AU - Lee, Sang Rae

AU - Hong, Chang Hyung

AU - Roh, Hyun Woong

PY - 2025/6

Y1 - 2025/6

N2 - 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 theamyloid/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.

AB - 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 theamyloid/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.

KW - Alzheimer’s disease

KW - Biomarker

KW - Endoplasmic reticulum stress

KW - Ex vivo study

KW - Fibroblast

UR - https://www.scopus.com/pages/publications/105008955563

U2 - 10.30773/pi.2025.0101

DO - 10.30773/pi.2025.0101

M3 - Article

AN - SCOPUS:105008955563

SN - 1738-3684

VL - 22

SP - 699

EP - 713

JO - Psychiatry Investigation

JF - Psychiatry Investigation

IS - 6

ER -

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

Abstract

Keywords

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