NAD+ modulates REST isoform expression and its downstream mitophagy in Alzheimer's disease.
Maria J Lagartos-Donate1, Beatriz Escobar-Doncel1, Caroline Shi-Qi Zhang1
1Department of Clinical Molecular Biology, University of Oslo (UiO) and Akershus University Hospital, Lørenskog, Norway.
Autophagy
|July 9, 2026
Summary
Repressor Element 1-Silencing Transcription factor (REST) supports neuronal function but declines in Alzheimer's disease (AD). Activating the NAD+-SIRT1 pathway restores REST, improving mitochondrial health and cognition in AD models.
Area of Science:
- Neuroscience
- Molecular Biology
- Metabolic Regulation
Background:
- Repressor Element 1-Silencing Transcription factor (REST) is a key regulator of neuronal function, impacting mitophagy, mitochondrial quality, and synaptic health.
- In Alzheimer's disease (AD), REST mislocalization and functional impairment correlate with early mitochondrial defects.
- The NAD+-SIRT1 pathway is implicated in cellular stress responses and aging.
Purpose of the Study:
- To investigate the role of REST in Alzheimer's disease pathogenesis.
- To explore the therapeutic potential of activating the NAD+-SIRT1 axis to restore REST function in AD models.
Main Methods:
- Utilized experimental models of Alzheimer's disease.
- Assessed REST localization and activity.
- Measured mitophagy, mitochondrial quality, and synaptic function markers.
- Analyzed the impact of NAD+-SIRT1 activation on REST-mediated gene programs and AD pathology.
Main Results:
- REST dysfunction and mislocalization were observed in experimental AD.
- Activation of the NAD+-SIRT1 axis successfully enhanced REST nuclear activity.
- Restored REST function led to improved mitochondrial quality and neuroprotection.
- Therapeutic intervention attenuated pathological hallmarks and cognitive deficits in AD models.
Conclusions:
- REST is a crucial, metabolism-sensitive regulator of mitochondrial and neuronal health.
- REST impairment contributes to Alzheimer's disease progression.
- Targeting the NAD+-SIRT1 axis represents a promising therapeutic strategy for Alzheimer's disease by restoring REST function.
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