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Neuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer’s disease-like pathology

Author

Listed:
  • Tal Nuriel

    (Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
    Columbia University Medical Center)

  • Sergio L. Angulo

    (The Robert F. Furchgott Center for Neural and Behavioral Science)

  • Usman Khan

    (Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
    Columbia University Medical Center)

  • Archana Ashok

    (Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
    Columbia University Medical Center)

  • Qiuying Chen

    (Weill Cornell Medical College)

  • Helen Y. Figueroa

    (Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
    Columbia University Medical Center)

  • Sheina Emrani

    (Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
    Columbia University Medical Center)

  • Li Liu

    (Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
    Columbia University Medical Center)

  • Mathieu Herman

    (Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
    Columbia University Medical Center)

  • Geoffrey Barrett

    (Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
    Columbia University Medical Center)

  • Valerie Savage

    (Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
    Columbia University Medical Center)

  • Luna Buitrago

    (The Robert F. Furchgott Center for Neural and Behavioral Science)

  • Efrain Cepeda-Prado

    (The Robert F. Furchgott Center for Neural and Behavioral Science)

  • Christine Fung

    (Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
    Columbia University Medical Center)

  • Eliana Goldberg

    (Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
    Columbia University Medical Center)

  • Steven S. Gross

    (Weill Cornell Medical College)

  • S. Abid Hussaini

    (Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
    Columbia University Medical Center)

  • Herman Moreno

    (The Robert F. Furchgott Center for Neural and Behavioral Science)

  • Scott A. Small

    (Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
    Columbia University Medical Center)

  • Karen E. Duff

    (Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
    Columbia University Medical Center
    New York State Psychiatric Institute)

Abstract

The ε4 allele of apolipoprotein E (APOE) is the dominant genetic risk factor for late-onset Alzheimer’s disease (AD). However, the reason APOE4 is associated with increased AD risk remains a source of debate. Neuronal hyperactivity is an early phenotype in both AD mouse models and in human AD, which may play a direct role in the pathogenesis of the disease. Here, we have identified an APOE4-associated hyperactivity phenotype in the brains of aged APOE mice using four complimentary techniques—fMRI, in vitro electrophysiology, in vivo electrophysiology, and metabolomics—with the most prominent hyperactivity occurring in the entorhinal cortex. Further analysis revealed that this neuronal hyperactivity is driven by decreased background inhibition caused by reduced responsiveness of excitatory neurons to GABAergic inhibitory inputs. Given the observations of neuronal hyperactivity in prodromal AD, we propose that this APOE4-driven hyperactivity may be a causative factor driving increased risk of AD among APOE4 carriers.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01444-0
    DOI: 10.1038/s41467-017-01444-0
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    Cited by:

    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. 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.
    3. 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.

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