Loss of REST associated with Alzheimer's disease pathology is ameliorated by NAD+

Downregulation and inactivation of the Repressor Element 1-Silencing Transcription factor (REST) is shown in Alzheimer's disease (AD) and likely contributes to its progression, but the exact molecular mechanism linking REST reduction to AD remains unclear. We examined changes in REST expression in the entorhinal cortex and hippocampus across different Braak stages of tauopathy. We show that alterations in REST expression and sub-cellular localization are partially responsible for AD pathology, as REST overexpression improves cognition, reduces amyloid-β and phosphorylated Tau deposition, and restores mitochondrial and synaptic homeostasis. Mechanistically, the NAD+/SIRT1 axis modulates REST expression through chromatin remodelling in the promoter region of REST, leading to changes in the expression of REST target genes involved in mitophagy and synaptic function. These findings reveal a new mechanism of action for NAD+ and highlight REST as a promising therapeutic target for AD therapy.

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Publication Details

Journal
Brain
Published
2025-07-23
DOI
https://doi.org/10.1093/brain/awaf261
Primary Topic
Nuclear Receptors and Signaling
Type
article
Field-Weighted Citation Impact
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article

Loss of REST associated with Alzheimer's disease pathology is ameliorated by NAD+

Alexander Anisimov, Bailei Li, Pingjie Wang, Domenica Caponio et al.
Brain
Nuclear Receptors and Signaling
article

Loss of REST associated with Alzheimer's disease pathology is ameliorated by NAD+

Alexander Anisimov, Bailei Li, Pingjie Wang, Domenica Caponio, Jie Pan, H. R. Nilsen, Vidar R. Jensen, Mariá José Lagartos-Donate, Rajeevkumar Raveendran Nair, Liu Shi, Nicola Montaldo, Shuqin Cao, N. González, Beatriz Escobar-Doncel, Alejo J. Nevado-Holgado, Lipeng Mao, Guobing Chen, Nuria Banzon-Pereira, Oscar Junhong Luo, Noel Buckley, Shi-qi Zhang
article en

Abstract

Downregulation and inactivation of the Repressor Element 1-Silencing Transcription factor (REST) is shown in Alzheimer's disease (AD) and likely contributes to its progression, but the exact molecular mechanism linking REST reduction to AD remains unclear. We examined changes in REST expression in the entorhinal cortex and hippocampus across different Braak stages of tauopathy. We show that alterations in REST expression and sub-cellular localization are partially responsible for AD pathology, as REST overexpression improves cognition, reduces amyloid-β and phosphorylated Tau deposition, and restores mitochondrial and synaptic homeostasis. Mechanistically, the NAD+/SIRT1 axis modulates REST expression through chromatin remodelling in the promoter region of REST, leading to changes in the expression of REST target genes involved in mitophagy and synaptic function. These findings reveal a new mechanism of action for NAD+ and highlight REST as a promising therapeutic target for AD therapy.

Brain
Oslo University Hospital (NO), Jinan University (CN), University of Oslo (NO), Akershus University Hospital (NO), University of Oxford (GB), NORCE Research AS (NO), Guangdong-Hongkong-Macau Joint Laboratory of Collaborative Innovation for Environmental Quality (CN), Neuroscience Institute (IT), Department of Embryology (US), First Affiliated Hospital of Zhengzhou University (CN), Redx Pharma (United Kingdom) (GB), Zhejiang University of Technology (CN), University of Castilla-La Mancha (ES)
Openalex Percentile: Top 33%
Nuclear Receptors and Signaling
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