Evaluation of SAMP8 Mice as a Model for Sleep-Wake and Rhythm Disturbances Associated with Alzheimer's Disease: Impact of Treatment with the Dual Orexin (Hypocretin) Receptor Antagonist Lemborexant.

Carsten T Beuckmann,Masahiro Bando,Margaret Moline,Erik S Musiek,Toshitaka Sato,Yoshihide Osada,Hiroyuki Suzuki,Takashi Ueno

doi:10.3233/jad-201054

Abstract

Background:Many patients with Alzheimer’s disease (AD) display circadian rhythm and sleep-wake disturbances. However, few mouse AD models exhibit these disturbances. Lemborexant, a dual orexin receptor antagonist, is under development for treating circadian rhythm disorders in dementia.Objective:Evaluation of senescence-accelerated mouse prone-8 (SAMP8) mice as a model for sleep-wake and rhythm disturbances in AD and the effect of lemborexant by assessing sleep-wake/diurnal rhythm behavior.Methods:SAMP8 and control senescence-accelerated mouse resistant-1 (SAMR1) mice received vehicle or lemborexant at light onset; plasma lemborexant and diurnal cerebrospinal fluid (CSF) orexin concentrations were assessed. Sleep-wake behavior and running wheel activity were evaluated.Results:Plasma lemborexant concentrations were similar between strains. The peak/nadir timing of CSF orexin concentrations were approximately opposite between strains. During lights-on, SAMP8 mice showed less non-rapid eye movement (non-REM) and REM sleep than SAMR1 mice. Lemborexant treatment normalized wakefulness/non-REM sleep in SAMP8 mice. During lights-off, lemborexant-treated SAMR1 mice showed increased non-REM sleep; lemborexant-treated SAMP8 mice displayed increased wakefulness. SAMP8 mice showed differences in electroencephalogram architecture versus SAMR1 mice. SAMP8 mice exhibited more running wheel activity during lights-on. Lemborexant treatment reduced activity during lights-on and increased activity in the latter half of lights-off, demonstrating a corrective effect on overall diurnal rhythm. Lemborexant delayed the acrophase of activity in both strains by approximately 1 hour.Conclusion:SAMP8 mice display several aspects of sleep-wake and rhythm disturbances in AD, notably mistimed activity. These findings provide some preclinical rationale for evaluating lemborexant in patients with AD who experience sleep-wake and rhythm disturbances.

Highlights

45% of patients with Alzheimer’s disease (AD) display circadian rhythm and sleepwake disturbances [1], which may precede overt cognitive impairments [2, 3]
We found that senescence-accelerated mouse prone-8 (SAMP8) mice had comparatively less rapid eye movement (REM) sleep in the lights-on period, resulting in an overall reduction in REM sleep time
Previous studies have shown that SAMP8 mice have memory/cognition deficits and brain pathologies resembling human AD [17]

Summary

Introduction

45% of patients with Alzheimer’s disease (AD) display circadian rhythm and sleepwake disturbances [1], which may precede overt cognitive impairments [2, 3] When these disturbances occur frequently, they can be collectively referred to as irregular sleep-wake rhythm disorder (ISWRD; ICD-10-CM code G47.23). Objective: Evaluation of senescence-accelerated mouse prone-8 (SAMP8) mice as a model for sleep-wake and rhythm disturbances in AD and the effect of lemborexant by assessing sleep-wake/diurnal rhythm behavior. Conclusion: SAMP8 mice display several aspects of sleep-wake and rhythm disturbances in AD, notably mistimed activity. These findings provide some preclinical rationale for evaluating lemborexant in patients with AD who experience sleep-wake and rhythm disturbances

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Conclusion