Aβ-induced degradation of BMAL1 and CBP leads to circadian rhythm disruption in Alzheimer's disease.

Hyundong Song,Kyungjin Kim,Han Kyoung Choe,Sehyung Cho,Inhee Mook-Jung,Dong-Hee Han,Minho Moon,Ahbin Kim,Changhwan Jang

doi:10.1186/s13024-015-0007-x

Abstract

BackgroundPatients with Alzheimer’s disease (AD) frequently experience disruption of their circadian rhythms, but whether and how circadian clock molecules are perturbed by AD remains unknown. AD is an age-related neurological disorder and amyloid-β (Aβ) is one of major causative molecules in the pathogenesis of AD.ResultsIn this study, we investigated the role of Aβ in the regulation of clock molecules and circadian rhythm using an AD mouse model. These mice exhibited altered circadian behavior, and altered expression patterns of the circadian clock genes, Bmal1 and Per2. Using cultured cells, we showed that Aβ induces post-translational degradation of the circadian clock regulator CBP, as well as the transcription factor BMAL1, which forms a complex with the master circadian transcription factor CLOCK. Aβ-induced degradation of BMAL1 and CBP correlated with the reduced binding of transcription factors to the Per2 promoter, which in turn resulted in disruptions to PER2 protein expression and the oscillation of Per2 mRNA levels.ConclusionsOur results elucidate the underlying mechanisms for disrupted circadian rhythm in AD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-015-0007-x) contains supplementary material, which is available to authorized users.

Highlights

Patients with Alzheimer’s disease (AD) frequently experience disruption of their circadian rhythms, but whether and how circadian clock molecules are perturbed by AD remains unknown
Abnormal circadian behavior in 5XFAD mice Since previous studies have reported that circadian rhythms are disrupted in AD patients as well as in AD mouse models [14,15,16,17], we conducted behavioral assays to determine whether the circadian rhythms of 5XFAD mice are impaired
Both young and old male mice, inserted with E-mitter probes, were entrained for one weeks to a 12 h:12 h Light–dark (LD) cycle with water and food available ad libitum. Their body temperature (BT) and home cage activity (HCA) were continuously measured at 6 min intervals, and their representative actograms are shown in Figure 1 and Additional file 1: Figure S1

Summary

Introduction

Patients with Alzheimer’s disease (AD) frequently experience disruption of their circadian rhythms, but whether and how circadian clock molecules are perturbed by AD remains unknown. AD is an age-related neurological disorder and amyloid-β (Aβ) is one of major causative molecules in the pathogenesis of AD. The physiological processes controlled by the circadian clock include sleep, hormone secretion, and glucose metabolism, which together determine daily circadian oscillation patterns. The circadian clock system maintains multiple circadian oscillators in various organs to promote homeostatic balance and adaptability to the Alzheimer’s disease (AD) is the most common agedependent neurodegenerative disease. Circadian rhythm disturbances are commonly reported in AD patients. More than 80% of AD patients over 65 years old suffer from circadian rhythm disorders, such as disturbances in thermoregulation and sleep-wake cycles [11,12]. Since circadian disturbance is often noted early in the onset of AD in people, it

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