Interneuron transcriptomics reveals pathologic markers of Alzheimer's disease progression

Kevin S Chen; Mohamed H Noureldein; Diana M Rigan; John M Hayes; Kyle J Loi; Junguk Hur; Masha G Savelieff; Eva L Feldman

doi:10.1016/j.nbd.2025.107012

Interneuron transcriptomics reveals pathologic markers of Alzheimer's disease progression

Neurobiol Dis. 2025 Jun 25:107012. doi: 10.1016/j.nbd.2025.107012. Online ahead of print.

Authors

Kevin S Chen¹, Mohamed H Noureldein², Diana M Rigan³, John M Hayes⁴, Kyle J Loi⁵, Junguk Hur⁶, Masha G Savelieff⁷, Eva L Feldman⁸

Affiliations

¹ Department 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. Electronic address: kechen@med.umich.edu.
² Department of Neurology, University of Michigan, Ann Arbor, MI, 48109, USA; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, 48109, USA. Electronic address: mnoureld@med.umich.edu.
³ Department of Neurology, University of Michigan, Ann Arbor, MI, 48109, USA; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, 48109, USA. Electronic address: drigan@med.umich.edu.
⁴ Department of Neurology, University of Michigan, Ann Arbor, MI, 48109, USA; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, 48109, USA. Electronic address: jmhayes@med.umich.edu.
⁵ Department of Neurology, University of Michigan, Ann Arbor, MI, 48109, USA; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, 48109, USA. Electronic address: kloi@med.umich.edu.
⁶ Department of Biomedical Sciences, University of North Dakota, Grand Forks, ND, 58202, USA. Electronic address: junguk.hur@med.und.edu.
⁷ Department of Biomedical Sciences, University of North Dakota, Grand Forks, ND, 58202, USA. Electronic address: masha.savelieff@ndus.edu.
⁸ Department of Neurology, University of Michigan, Ann Arbor, MI, 48109, USA; NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, 48109, USA. Electronic address: efeldman@umich.edu.

PMID: 40578769
DOI: 10.1016/j.nbd.2025.107012

Abstract

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.

Keywords: 5XFAD; Excitatory; Hyperexcitability; Inhibitory; Mouse; Spatial transcriptomics.