Proinflammatory transcriptomic and kinomic alterations in astrocytes derived from patients with familial Alzheimer's disease
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by profound neuronal and cognitive decline, with increasing evidence implicating astrocyte dysfunction in disease pathology. While traditional therapeutic approaches have primarily targeted neurons, the crucial r...
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Elsevier
2025-08-01
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| Series: | Brain, Behavior, & Immunity - Health |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666354625001024 |
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| author | Benjamin Siciliano Nicholas D. Henkel William G. Ryan V Ali Sajid Imami John M. Vergis Chongchong Xu Taylen O. Arvay Smita Sahay Priyanka Pulvender Abdul-rizaq Hamoud Chadwick Hales Robert E. McCullumsmith Zhexing Wen |
| author_facet | Benjamin Siciliano Nicholas D. Henkel William G. Ryan V Ali Sajid Imami John M. Vergis Chongchong Xu Taylen O. Arvay Smita Sahay Priyanka Pulvender Abdul-rizaq Hamoud Chadwick Hales Robert E. McCullumsmith Zhexing Wen |
| author_sort | Benjamin Siciliano |
| collection | DOAJ |
| description | Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by profound neuronal and cognitive decline, with increasing evidence implicating astrocyte dysfunction in disease pathology. While traditional therapeutic approaches have primarily targeted neurons, the crucial role of astrocytes in metabolism, neurotransmission, amyloid-beta clearance, and neuroinflammation underscores their potential as therapeutic targets. In this study, we employed a multiomic integrative analysis combining transcriptomic and kinomic profiling of human induced pluripotent stem cell (hiPSC)-derived astrocytes from patients with familial AD (fAD) compared to healthy controls (HCs). Our transcriptomic analysis identified 1249 significantly differentially expressed genes, highlighting a pronounced upregulation of inflammatory genes (SERPINA3, IL6R, IL1RAP, TNFRSF11A) and a concomitant downregulation of genes essential for synaptic support and ion channel function (STMN2, NMNAT2, SCN2A, GRIN1). Kinomic profiling revealed dysregulated kinase activities within DYRK, GSK, and MAPK families, further implicating altered kinase signaling pathways in astrocyte dysfunction. Integration of these datasets pinpointed critical molecular hubs, notably within the PI3K signaling and inflammatory pathways, highlighting targets such as JAK2, STAT3, and AKT1 as potential modulators of disease progression. Furthermore, leveraging the Library of Integrated Network-Based Cellular Signatures (LINCS) platform, we identified chemical perturbagens, including fluticasone propionate and Akt inhibitors, capable of reversing the transcriptomic signatures associated with fAD astrocytes. This integrative multiomic approach not only enhances our understanding of astrocyte-specific molecular mechanisms in AD but also provides novel targets for therapeutic intervention aimed at mitigating astrocyte-driven neurodegeneration. |
| format | Article |
| id | doaj-art-455dc11de87845d7bd752e30d76e8cf4 |
| institution | Matheson Library |
| issn | 2666-3546 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Brain, Behavior, & Immunity - Health |
| spelling | doaj-art-455dc11de87845d7bd752e30d76e8cf42025-07-30T04:17:45ZengElsevierBrain, Behavior, & Immunity - Health2666-35462025-08-0147101044Proinflammatory transcriptomic and kinomic alterations in astrocytes derived from patients with familial Alzheimer's diseaseBenjamin Siciliano0Nicholas D. Henkel1William G. Ryan V2Ali Sajid Imami3John M. Vergis4Chongchong Xu5Taylen O. Arvay6Smita Sahay7Priyanka Pulvender8Abdul-rizaq Hamoud9Chadwick Hales10Robert E. McCullumsmith11Zhexing Wen12The Graduate Program in Molecular and Systems Pharmacology, Emory University, Atlanta, GA, United StatesDepartment of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United StatesDepartment of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United StatesDepartment of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United StatesDepartment of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United StatesDepartment of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United StatesDepartment of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United StatesDepartment of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United StatesDepartment of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United StatesDepartment of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United StatesDepartment of Neurology, Emory University School of Medicine, Atlanta, GA, United States; Emory Goizueta Alzheimer's Disease Research Center, Emory University, Atlanta, GA, United States; Center for Neurodegenerative Disease, Emory University, Atlanta, GA, United StatesDepartment of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States; Neurosciences Institute, ProMedica, Toledo, OH, United States; Corresponding author. Department of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States.Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States; Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States; Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, United States; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, United States; Corresponding author. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Georgia, Atlanta, United States.Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by profound neuronal and cognitive decline, with increasing evidence implicating astrocyte dysfunction in disease pathology. While traditional therapeutic approaches have primarily targeted neurons, the crucial role of astrocytes in metabolism, neurotransmission, amyloid-beta clearance, and neuroinflammation underscores their potential as therapeutic targets. In this study, we employed a multiomic integrative analysis combining transcriptomic and kinomic profiling of human induced pluripotent stem cell (hiPSC)-derived astrocytes from patients with familial AD (fAD) compared to healthy controls (HCs). Our transcriptomic analysis identified 1249 significantly differentially expressed genes, highlighting a pronounced upregulation of inflammatory genes (SERPINA3, IL6R, IL1RAP, TNFRSF11A) and a concomitant downregulation of genes essential for synaptic support and ion channel function (STMN2, NMNAT2, SCN2A, GRIN1). Kinomic profiling revealed dysregulated kinase activities within DYRK, GSK, and MAPK families, further implicating altered kinase signaling pathways in astrocyte dysfunction. Integration of these datasets pinpointed critical molecular hubs, notably within the PI3K signaling and inflammatory pathways, highlighting targets such as JAK2, STAT3, and AKT1 as potential modulators of disease progression. Furthermore, leveraging the Library of Integrated Network-Based Cellular Signatures (LINCS) platform, we identified chemical perturbagens, including fluticasone propionate and Akt inhibitors, capable of reversing the transcriptomic signatures associated with fAD astrocytes. This integrative multiomic approach not only enhances our understanding of astrocyte-specific molecular mechanisms in AD but also provides novel targets for therapeutic intervention aimed at mitigating astrocyte-driven neurodegeneration.http://www.sciencedirect.com/science/article/pii/S2666354625001024Alzheimer's diseaseFamilial Alzheimer's diseaseAstrocyte dysfunctionMultiomic analysisTranscriptomicsKinomics |
| spellingShingle | Benjamin Siciliano Nicholas D. Henkel William G. Ryan V Ali Sajid Imami John M. Vergis Chongchong Xu Taylen O. Arvay Smita Sahay Priyanka Pulvender Abdul-rizaq Hamoud Chadwick Hales Robert E. McCullumsmith Zhexing Wen Proinflammatory transcriptomic and kinomic alterations in astrocytes derived from patients with familial Alzheimer's disease Brain, Behavior, & Immunity - Health Alzheimer's disease Familial Alzheimer's disease Astrocyte dysfunction Multiomic analysis Transcriptomics Kinomics |
| title | Proinflammatory transcriptomic and kinomic alterations in astrocytes derived from patients with familial Alzheimer's disease |
| title_full | Proinflammatory transcriptomic and kinomic alterations in astrocytes derived from patients with familial Alzheimer's disease |
| title_fullStr | Proinflammatory transcriptomic and kinomic alterations in astrocytes derived from patients with familial Alzheimer's disease |
| title_full_unstemmed | Proinflammatory transcriptomic and kinomic alterations in astrocytes derived from patients with familial Alzheimer's disease |
| title_short | Proinflammatory transcriptomic and kinomic alterations in astrocytes derived from patients with familial Alzheimer's disease |
| title_sort | proinflammatory transcriptomic and kinomic alterations in astrocytes derived from patients with familial alzheimer s disease |
| topic | Alzheimer's disease Familial Alzheimer's disease Astrocyte dysfunction Multiomic analysis Transcriptomics Kinomics |
| url | http://www.sciencedirect.com/science/article/pii/S2666354625001024 |
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