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Integrating peripheral blood and brain transcriptomics to identify immunological features associated with Alzheimer's disease in mild cognitive impairment patients.
Front Immunol. 2022; 13:986346.FI

Abstract

Background

Immune system dysfunction has been proven to be an important pathological event in Alzheimer's disease (AD). Mild cognitive impairment (MCI), as a transitional stage between normal cognitive function and AD, was an important research object for the screening of early diagnostic markers and therapeutic targets for AD. However, systematic assessment of peripheral immune system changes in MCI patients and consistent analysis with that in the CNS were still lacking.

Methods

Peripheral blood transcriptome data from the AddNeuroMed Cohort (n = 711) was used as a training dataset to assess the abundance of 24 immune cells through ImmuCellAI and to identify MCI-related immune signaling pathways and hub genes. The expression level of the immune hub gene was validated in peripheral blood (n = 587) and brain tissue (78 entorhinal cortex, 140 hippocampi, 91 temporal cortex, and 232 frontal cortex) validation datasets. Finally, reliable immune hub genes were applied for Gene Set Enrichment Analysis and correlation analysis of AD pathological characteristics.

Results

MCI patients have early changes in the abundance of various types of immune cells in peripheral blood, accompanied by significant changes in NF-kB, TNF, JAK-STAT, and MAPK signaling pathways. Five hub immune-related differentially expressed genes (NFKBIA, CD4, RELA, CASP3, and HSP90AA1) were screened by the cytoHubba plugin in Cytoscape and the least absolute shrinkage and selection operator (LASSO) regression. Their expression levels were significantly correlated with infiltration score and the abundance of monocytes, natural killer cells, Th2 T cells, T follicular helper cells, and cytotoxic T cells. After validation with independent datasets derived from peripheral blood and brain, RELA and HSP90AA1 were identified as two reliable immune hub genes in MCI patients and had consistent changes in AD. The Gene Set Enrichment Analysis (GSEA) showed that their expression levels were closely associated with Alzheimer's disease, JAK-STAT, calcium signaling pathway, etc. In addition, the expression level of RELA was positively correlated with β- and γ-secretase activity and Braak stage. The expression level of HSP90AA1 was negatively correlated with α- and β-secretase activity.

Conclusion

Immune system dysfunction was an early event in AD. It provides a new target for the early diagnosis and treatment of AD.

Links

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Authors+Show Affiliations

Qian XH
Department of Neurology and Institute of Neurology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Liu XL
Department of Neurology, Shanghai Fengxian District Central Hospital, Shanghai Jiao Tong University Affiliated Sixth People's Hospital South Campus, Shanghai, China.
Chen SD
Department of Neurology and Institute of Neurology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Tang HD
Department of Neurology and Institute of Neurology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Medical Center on Aging of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

MeSH

Alzheimer DiseaseAmyloid Precursor Protein SecretasesBrainCaspase 3Cognitive DysfunctionHumansNF-kappa BTranscriptome

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

36159817

Citation

Qian, Xiao-Hang, et al. "Integrating Peripheral Blood and Brain Transcriptomics to Identify Immunological Features Associated With Alzheimer's Disease in Mild Cognitive Impairment Patients." Frontiers in Immunology, vol. 13, 2022, p. 986346.
Qian XH, Liu XL, Chen SD, et al. Integrating peripheral blood and brain transcriptomics to identify immunological features associated with Alzheimer's disease in mild cognitive impairment patients. Front Immunol. 2022;13:986346.
Qian, X. H., Liu, X. L., Chen, S. D., & Tang, H. D. (2022). Integrating peripheral blood and brain transcriptomics to identify immunological features associated with Alzheimer's disease in mild cognitive impairment patients. Frontiers in Immunology, 13, 986346. https://doi.org/10.3389/fimmu.2022.986346
Qian XH, et al. Integrating Peripheral Blood and Brain Transcriptomics to Identify Immunological Features Associated With Alzheimer's Disease in Mild Cognitive Impairment Patients. Front Immunol. 2022;13:986346. PubMed PMID: 36159817.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Integrating peripheral blood and brain transcriptomics to identify immunological features associated with Alzheimer's disease in mild cognitive impairment patients. AU - Qian,Xiao-Hang, AU - Liu,Xiao-Li, AU - Chen,Sheng-di, AU - Tang,Hui-Dong, Y1 - 2022/09/09/ PY - 2022/07/05/received PY - 2022/08/15/accepted PY - 2022/9/26/entrez PY - 2022/9/27/pubmed PY - 2022/9/28/medline KW - Alzheimer’s disease KW - HSP90AA1 KW - RELA KW - immune hub gene KW - mild cognitive impairment KW - peripheral immune cells SP - 986346 EP - 986346 JF - Frontiers in immunology JO - Front Immunol VL - 13 N2 - Background: Immune system dysfunction has been proven to be an important pathological event in Alzheimer's disease (AD). Mild cognitive impairment (MCI), as a transitional stage between normal cognitive function and AD, was an important research object for the screening of early diagnostic markers and therapeutic targets for AD. However, systematic assessment of peripheral immune system changes in MCI patients and consistent analysis with that in the CNS were still lacking. Methods: Peripheral blood transcriptome data from the AddNeuroMed Cohort (n = 711) was used as a training dataset to assess the abundance of 24 immune cells through ImmuCellAI and to identify MCI-related immune signaling pathways and hub genes. The expression level of the immune hub gene was validated in peripheral blood (n = 587) and brain tissue (78 entorhinal cortex, 140 hippocampi, 91 temporal cortex, and 232 frontal cortex) validation datasets. Finally, reliable immune hub genes were applied for Gene Set Enrichment Analysis and correlation analysis of AD pathological characteristics. Results: MCI patients have early changes in the abundance of various types of immune cells in peripheral blood, accompanied by significant changes in NF-kB, TNF, JAK-STAT, and MAPK signaling pathways. Five hub immune-related differentially expressed genes (NFKBIA, CD4, RELA, CASP3, and HSP90AA1) were screened by the cytoHubba plugin in Cytoscape and the least absolute shrinkage and selection operator (LASSO) regression. Their expression levels were significantly correlated with infiltration score and the abundance of monocytes, natural killer cells, Th2 T cells, T follicular helper cells, and cytotoxic T cells. After validation with independent datasets derived from peripheral blood and brain, RELA and HSP90AA1 were identified as two reliable immune hub genes in MCI patients and had consistent changes in AD. The Gene Set Enrichment Analysis (GSEA) showed that their expression levels were closely associated with Alzheimer's disease, JAK-STAT, calcium signaling pathway, etc. In addition, the expression level of RELA was positively correlated with β- and γ-secretase activity and Braak stage. The expression level of HSP90AA1 was negatively correlated with α- and β-secretase activity. Conclusion: Immune system dysfunction was an early event in AD. It provides a new target for the early diagnosis and treatment of AD. SN - 1664-3224 UR - https://www.unboundmedicine.com/medline/citation/36159817/Integrating_peripheral_blood_and_brain_transcriptomics_to_identify_immunological_features_associated_with_Alzheimer's_disease_in_mild_cognitive_impairment_patients_ DB - PRIME DP - Unbound Medicine ER -