IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-52297-3.html
   My bibliography  Save this article

Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology

Author

Listed:
  • Annie M. Goettemoeller

    (Emory University School of Medicine
    Emory University)

  • Emmie Banks

    (Emory University School of Medicine
    Emory University)

  • Prateek Kumar

    (Yale University)

  • Viktor J. Olah

    (Emory University School of Medicine)

  • Katharine E. McCann

    (Emory University School of Medicine)

  • Kelly South

    (Emory University School of Medicine
    Emory University)

  • Christina C. Ramelow

    (Emory University
    Emory University School of Medicine)

  • Anna Eaton

    (Georgia Institute of Technology)

  • Duc M. Duong

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

  • Nicholas T. Seyfried

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

  • David Weinshenker

    (Emory University School of Medicine)

  • Srikant Rangaraju

    (Yale University)

  • Matthew J. M. Rowan

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

Abstract

Preventative treatment for Alzheimer’s Disease (AD) is dire, yet mechanisms underlying early regional vulnerability remain unknown. In AD, one of the earliest pathophysiological correlates to cognitive decline is hyperexcitability, which is observed first in the entorhinal cortex. Why hyperexcitability preferentially emerges in specific regions in AD is unclear. Using regional, cell-type-specific proteomics and electrophysiology in wild-type mice, we uncovered a unique susceptibility of the entorhinal cortex to human amyloid precursor protein (hAPP). Entorhinal hyperexcitability resulted from selective vulnerability of parvalbumin (PV) interneurons, with respect to surrounding excitatory neurons. This effect was partially replicated with an APP chimera containing a humanized amyloid-beta sequence. EC hyperexcitability could be ameliorated by co-expression of human Tau with hAPP at the expense of increased pathological tau species, or by enhancing PV interneuron excitability in vivo. This study suggests early interventions targeting inhibitory neurons may protect vulnerable regions from the effects of APP/amyloid and tau pathology.

Suggested Citation

  • Annie M. Goettemoeller & Emmie Banks & Prateek Kumar & Viktor J. Olah & Katharine E. McCann & Kelly South & Christina C. Ramelow & Anna Eaton & Duc M. Duong & Nicholas T. Seyfried & David Weinshenker , 2024. "Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52297-3
    DOI: 10.1038/s41467-024-52297-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-52297-3
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-52297-3?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Tal Nuriel & Sergio L. Angulo & Usman Khan & Archana Ashok & Qiuying Chen & Helen Y. Figueroa & Sheina Emrani & Li Liu & Mathieu Herman & Geoffrey Barrett & Valerie Savage & Luna Buitrago & Efrain Cep, 2017. "Neuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer’s disease-like pathology," Nature Communications, Nature, vol. 8(1), pages 1-14, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Ahrum Son & Hyunsoo Kim & Jolene K. Diedrich & Casimir Bamberger & Daniel B. McClatchy & Stuart A. Lipton & John R. Yates, 2024. "Using in vivo intact structure for system-wide quantitative analysis of changes in proteins," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. 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.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52297-3. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.