Zolpidem restores sleep and decreases amyloid in a mouse model.

Abstract

INTRODUCTION: Deficits in non-rapid eye movement (NREM) sleep facilitate Alzheimer's disease (AD) progression. Enhancing gamma-aminobutyric acid-ergic (GABAergic) signaling can restore sleep. Unbiased computational analysis identified zolpidem as high-affinity GABA receptor modulator facilitating chloride transport that could slow AD. METHODS: Zolpidem's effects on sleep and Alzheimer's progression were evaluated in young APP/PS1 (amyloid precursor protein/presenilin 1) mice. Sleep was monitored with electroencephalography/electromyography (EEG/EMG) telemetry. Wide-field imaging with voltage-sensitive dyes (VSDs) was used to track sleep-dependent brain rhythms. Multiphoton microscopy allowed assessments of amyloid plaque load and basal neuronal calcium levels. Behavioral assays were used to measure memory and cognitive function. RESULTS: Zolpidem restored NREM sleep and rescued sleep-dependent brain rhythm, slow oscillation. Zolpidem administration reduced cortical amyloid plaque burden, mitigated neuronal calcium overload, and enhanced sleep-dependent contextual recall without adverse effects on locomotion. DISCUSSION: Zolpidem effectively decreased amyloid in young APP/PS1 mice. This supports zolpidem's therapeutic promise as an intervention strategy at early stages of AD. HIGHLIGHTS: Zolpidem treatment improves non-rapid eye movement (NREM) sleep stability and reduces sleep fragmentation. Zolpidem restores slow oscillation in young APP/PS1 (amyloid precursor protein/presenilin 1) mice. Zolpidem treatment reduces amyloid plaque burden and calcium overload in neurons. Zolpidem-treated mice show improved sleep-dependent memory consolidation. Sleep rhythm enhancement shows promise for Alzheimer's therapy.