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bioRxiv · 10.1101/2025.08.31.673377

Zolpidem restores sleep and slows Alzheimer's progression in a mouse model

Yu, L.·Yokomizo, S.·Doan, T. H.·Zhao, Q.·Ganne, A.·Balasubramaniam, M.·Kastanenka, K. V.
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Abstract

STRUCTURED ABSTRACTO_ST_ABSINTRODUCTIONC_ST_ABSDeficits in Non-Rapid Eye Movement (NREM) sleep facilitate Alzheimers disease (AD) progression. Enhancing GABAergic signaling can restore sleep. Unbiased computational analysis identified zolpidem as high-affinity GABA receptor modulator facilitating chloride transport that could slow AD. METHODSZolpidems effects on sleep and Alzheimers progression were evaluated in young APP/PS1 mice. Sleep was monitored with EEG/EMG telemetry. Widefield imaging with voltage-sensitive dyes 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. RESULTSZolpidem 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 memory consolidation without adverse effects on locomotion. DISCUSSIONZolpidem effectively slowed Alzheimers progression in young APP/PS1 mice. This supports zolpidems therapeutic promise as an intervention strategy at early stages of AD.

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Yu, L., Yokomizo, S., Doan, T. H., Zhao, Q., Ganne, A., Balasubramaniam, M., Kastanenka, K. V.. 2025-09-04. Zolpidem restores sleep and slows Alzheimer's progression in a mouse model. https://doi.org/10.1101/2025.08.31.673377

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