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Native-state proteomics of Parvalbumin interneurons identifies unique molecular signatures and vulnerabilities to early Alzheimer’s pathology

Author

Listed:
  • Prateek Kumar

    (Emory University School of Medicine
    Emory University School of Medicine
    Yale University School of Medicine)

  • Annie M. Goettemoeller

    (Emory University School of Medicine
    Emory University)

  • Claudia Espinosa-Garcia

    (Emory University School of Medicine
    Yale University School of Medicine)

  • Brendan R. Tobin

    (Georgia Institute of Technology)

  • Ali Tfaily

    (Yale University School of Medicine)

  • Ruth S. Nelson

    (Yale University School of Medicine)

  • Aditya Natu

    (Emory University School of Medicine)

  • Eric B. Dammer

    (Emory University School of Medicine
    Emory University)

  • Juliet V. Santiago

    (Emory University School of Medicine
    Emory University School of Medicine
    Emory University)

  • Sneha Malepati

    (Emory University School of Medicine
    Emory University School of Medicine)

  • Lihong Cheng

    (Emory University School of Medicine
    Emory University School of Medicine)

  • Hailian Xiao

    (Emory University School of Medicine
    Emory University School of Medicine)

  • Duc D. Duong

    (Emory University School of Medicine
    Emory University)

  • Nicholas T. Seyfried

    (Emory University School of Medicine
    Emory University School of Medicine
    Emory University)

  • Levi B. Wood

    (Georgia Institute of Technology
    GeoInsrgia titute of Technology)

  • Matthew J. M. Rowan

    (Emory University School of Medicine
    Emory University School of Medicine)

  • Srikant Rangaraju

    (Emory University School of Medicine
    Emory University School of Medicine
    Yale University School of Medicine)

Abstract

Dysfunction in fast-spiking parvalbumin interneurons (PV-INs) may represent an early pathophysiological perturbation in Alzheimer’s Disease (AD). Defining early proteomic alterations in PV-INs can provide key biological and translationally-relevant insights. We used cell-type-specific in-vivo biotinylation of proteins (CIBOP) coupled with mass spectrometry to obtain native-state PV-IN proteomes. PV-IN proteomic signatures include high metabolic and translational activity, with over-representation of AD-risk and cognitive resilience-related proteins. In bulk proteomes, PV-IN proteins were associated with cognitive decline in humans, and with progressive neuropathology in humans and the 5xFAD mouse model of Aβ pathology. PV-IN CIBOP in early stages of Aβ pathology revealed signatures of increased mitochondria and metabolism, synaptic and cytoskeletal disruption and decreased mTOR signaling, not apparent in whole-brain proteomes. Furthermore, we demonstrated pre-synaptic defects in PV-to-excitatory neurotransmission, validating our proteomic findings. Overall, in this study we present native-state proteomes of PV-INs, revealing molecular insights into their unique roles in cognitive resiliency and AD pathogenesis.

Suggested Citation

  • Prateek Kumar & Annie M. Goettemoeller & Claudia Espinosa-Garcia & Brendan R. Tobin & Ali Tfaily & Ruth S. Nelson & Aditya Natu & Eric B. Dammer & Juliet V. Santiago & Sneha Malepati & Lihong Cheng & , 2024. "Native-state proteomics of Parvalbumin interneurons identifies unique molecular signatures and vulnerabilities to early Alzheimer’s pathology," Nature Communications, Nature, vol. 15(1), pages 1-26, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47028-7
    DOI: 10.1038/s41467-024-47028-7
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