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

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. Wolfe, David A. Bennett, Eunjung A. Lee and Bruce A. Yankner ()
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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

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42704-6

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