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A neurodegeneration checkpoint mediated by REST protects against the onset of Alzheimer’s disease

Author

Listed:
  • Liviu Aron

    (Department of Genetics, Harvard Medical School)

  • Chenxi Qiu

    (Department of Genetics, Harvard Medical School)

  • Zhen Kai Ngian

    (Department of Genetics, Harvard Medical School)

  • Marianna Liang

    (Department of Genetics, Harvard Medical School)

  • Derek Drake

    (Department of Genetics, Harvard Medical School)

  • Jaejoon Choi

    (Department of Genetics, Harvard Medical School)

  • Marty A. Fernandez

    (Brigham and Women’s Hospital)

  • Perle Roche

    (Department of Genetics, Harvard Medical School)

  • Emma L. Bunting

    (Department of Genetics, Harvard Medical School)

  • Ella K. Lacey

    (Department of Genetics, Harvard Medical School)

  • Sara E. Hamplova

    (Department of Genetics, Harvard Medical School)

  • Monlan Yuan

    (Department of Genetics, Harvard Medical School)

  • Michael S. Wolfe

    (Brigham and Women’s Hospital)

  • David A. Bennett

    (Rush University Medical Center)

  • Eunjung A. Lee

    (Boston Children’s Hospital)

  • Bruce A. Yankner

    (Department of Genetics, Harvard Medical School)

Abstract

Many aging individuals accumulate the pathology of Alzheimer’s disease (AD) without evidence of cognitive decline. Here we describe an integrated neurodegeneration checkpoint response to early pathological changes that restricts further disease progression and preserves cognitive function. Checkpoint activation is mediated by the REST transcriptional repressor, which is induced in cognitively-intact aging humans and AD mouse models at the onset of amyloid β-protein (Aβ) deposition and tau accumulation. REST induction is mediated by the unfolded protein response together with β-catenin signaling. A consequence of this response is the targeting of REST to genes involved in key pathogenic pathways, resulting in downregulation of gamma secretase, tau kinases, and pro-apoptotic proteins. Deletion of REST in the 3xTg and J20 AD mouse models accelerates Aβ deposition and the accumulation of misfolded and phosphorylated tau, leading to neurodegeneration and cognitive decline. Conversely, viral-mediated overexpression of REST in the hippocampus suppresses Aβ and tau pathology. Thus, REST mediates a neurodegeneration checkpoint response with multiple molecular targets that may protect against the onset of AD.

Suggested Citation

  • Liviu Aron & Chenxi Qiu & Zhen Kai Ngian & Marianna Liang & Derek Drake & Jaejoon Choi & Marty A. Fernandez & Perle Roche & Emma L. Bunting & Ella K. Lacey & Sara E. Hamplova & Monlan Yuan & Michael S, 2023. "A neurodegeneration checkpoint mediated by REST protects against the onset of Alzheimer’s disease," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42704-6
    DOI: 10.1038/s41467-023-42704-6
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    References listed on IDEAS

    as
    1. Tao Lu & Liviu Aron & Joseph Zullo & Ying Pan & Haeyoung Kim & Yiwen Chen & Tun-Hsiang Yang & Hyun-Min Kim & Derek Drake & X. Shirley Liu & David A. Bennett & Monica P. Colaiácovo & Bruce A. Yankner, 2014. "REST and stress resistance in ageing and Alzheimer’s disease," Nature, Nature, vol. 507(7493), pages 448-454, March.
    2. Shih-Min A. Huang & Yuji M. Mishina & Shanming Liu & Atwood Cheung & Frank Stegmeier & Gregory A. Michaud & Olga Charlat & Elizabeth Wiellette & Yue Zhang & Stephanie Wiessner & Marc Hild & Xiaoying S, 2009. "Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling," Nature, Nature, vol. 461(7264), pages 614-620, October.
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