Interneuron transcriptomics reveals pathologic markers of Alzheimer's disease progression
Alzheimer's disease (AD) exhibits imbalance between neuronal excitation and inhibition, likely secondary to interneuron dysfunction. To reveal underlying mediators, we spatially profiled the transcriptome of neuronal subtypes in 5XFAD versus control mice at early- and late-stage disease. Pooled...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-09-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125002281 |
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| author | Kevin S. Chen Mohamed H. Noureldein Diana M. Rigan John M. Hayes Kyle J. Loi Junguk Hur Masha G. Savelieff Eva L. Feldman |
| author_facet | Kevin S. Chen Mohamed H. Noureldein Diana M. Rigan John M. Hayes Kyle J. Loi Junguk Hur Masha G. Savelieff Eva L. Feldman |
| author_sort | Kevin S. Chen |
| collection | DOAJ |
| description | Alzheimer's disease (AD) exhibits imbalance between neuronal excitation and inhibition, likely secondary to interneuron dysfunction. To reveal underlying mediators, we spatially profiled the transcriptome of neuronal subtypes in 5XFAD versus control mice at early- and late-stage disease. Pooled analysis of neuron types showed expected pathways at early-stage (RNA and protein processing pathways) versus late-stage (neurodegenerative pathways) disease. Early-stage interneurons exhibited alterations in AD-related RNA and protein pathways along with canonical neurodegenerative pathways. Early-stage excitatory neurons, however, showed changes in axon guidance and synapse pathways, without representation of neurodegenerative pathways. Classical neurodegenerative pathways were represented only in late-stage excitatory neurons. Late-stage interneurons instead featured neuronal and synapse pathways along with cellular, cancer, and infection pathways. Our results suggest earlier neurodegenerative pathway involvement in interneurons, represented in excitatory neurons only at later stages, possibly indicating earlier inhibitory neuron involvement. These transcriptomic profiles offer insight into potential AD pathophysiology and therapeutic targets. |
| format | Article |
| id | doaj-art-7417ffbea7d64764b7f8a77046b78200 |
| institution | Kabale University |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-7417ffbea7d64764b7f8a77046b782002025-08-20T03:32:23ZengElsevierNeurobiology of Disease1095-953X2025-09-0121310701210.1016/j.nbd.2025.107012Interneuron transcriptomics reveals pathologic markers of Alzheimer's disease progressionKevin S. Chen0Mohamed H. Noureldein1Diana M. Rigan2John M. Hayes3Kyle J. Loi4Junguk Hur5Masha G. Savelieff6Eva L. Feldman7Department of Neurology, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Neurosurgery, University of Michigan, Ann Arbor, MI, 48109, USA; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, 48109, USADepartment of Neurology, University of Michigan, Ann Arbor, MI, 48109, USA; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, 48109, USADepartment of Neurology, University of Michigan, Ann Arbor, MI, 48109, USA; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, 48109, USADepartment of Neurology, University of Michigan, Ann Arbor, MI, 48109, USA; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, 48109, USADepartment of Neurology, University of Michigan, Ann Arbor, MI, 48109, USA; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, 48109, USADepartment of Biomedical Sciences, University of North Dakota, Grand Forks, ND, 58202, USADepartment of Biomedical Sciences, University of North Dakota, Grand Forks, ND, 58202, USADepartment of Neurology, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Neurosurgery, University of Michigan, Ann Arbor, MI, 48109, USA; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, 48109, USA; Corresponding author at: 5017 AAT-BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA.Alzheimer's disease (AD) exhibits imbalance between neuronal excitation and inhibition, likely secondary to interneuron dysfunction. To reveal underlying mediators, we spatially profiled the transcriptome of neuronal subtypes in 5XFAD versus control mice at early- and late-stage disease. Pooled analysis of neuron types showed expected pathways at early-stage (RNA and protein processing pathways) versus late-stage (neurodegenerative pathways) disease. Early-stage interneurons exhibited alterations in AD-related RNA and protein pathways along with canonical neurodegenerative pathways. Early-stage excitatory neurons, however, showed changes in axon guidance and synapse pathways, without representation of neurodegenerative pathways. Classical neurodegenerative pathways were represented only in late-stage excitatory neurons. Late-stage interneurons instead featured neuronal and synapse pathways along with cellular, cancer, and infection pathways. Our results suggest earlier neurodegenerative pathway involvement in interneurons, represented in excitatory neurons only at later stages, possibly indicating earlier inhibitory neuron involvement. These transcriptomic profiles offer insight into potential AD pathophysiology and therapeutic targets.http://www.sciencedirect.com/science/article/pii/S09699961250022815XFADExcitatoryHyperexcitabilityInhibitoryMouseSpatial transcriptomics |
| spellingShingle | Kevin S. Chen Mohamed H. Noureldein Diana M. Rigan John M. Hayes Kyle J. Loi Junguk Hur Masha G. Savelieff Eva L. Feldman Interneuron transcriptomics reveals pathologic markers of Alzheimer's disease progression Neurobiology of Disease 5XFAD Excitatory Hyperexcitability Inhibitory Mouse Spatial transcriptomics |
| title | Interneuron transcriptomics reveals pathologic markers of Alzheimer's disease progression |
| title_full | Interneuron transcriptomics reveals pathologic markers of Alzheimer's disease progression |
| title_fullStr | Interneuron transcriptomics reveals pathologic markers of Alzheimer's disease progression |
| title_full_unstemmed | Interneuron transcriptomics reveals pathologic markers of Alzheimer's disease progression |
| title_short | Interneuron transcriptomics reveals pathologic markers of Alzheimer's disease progression |
| title_sort | interneuron transcriptomics reveals pathologic markers of alzheimer s disease progression |
| topic | 5XFAD Excitatory Hyperexcitability Inhibitory Mouse Spatial transcriptomics |
| url | http://www.sciencedirect.com/science/article/pii/S0969996125002281 |
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