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

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.

Cell-Autonomous Regulation of Astrocyte Activation by the Circadian Clock Protein BMAL1

“…Thus, dampening the rhythmicity of BMAL1 expression through circadian clock disruption likely plays a role in mediating astrogliosis, perhaps by restricting BMAL1 levels at certain key times of day. BMAL1 levels can be suppressed by several factors such as aging (Wyse and Coogan, 2010), inflammation (Curtis et al, 2015), or amyloid-beta (Song et al, 2015), all of which could potentially influence astrocyte activation and function in a BMAL1-dependent manner.…”

“…The core clock regulates transcription of thousands of genes in a highly tissue-specific manner, regulating cellular functions including metabolism, inflammation, and redox homeostasis (Bass and Takahashi, 2010). In addition to disrupted activity and sleep rhythms, dysregulated circadian gene expression patterns are also observed in neurodegenerative disease models and patients (Song et al, 2015; Breen et al, 2014; Cronin et al, 2017). However, the impact of clock dysfunction on neurological diseases of the brain remains poorly understood.…”

Circadian alterations during early stages of Alzheimer's disease are associated with aberrant cycles of DNA methylation in BMAL1

“…With respect to other disease specific changes in AD, BMAL1 protein levels may be directly affected by accumulation of amyloid-β (Aβ) during the course of AD pathology. A recent study reported that Aβ enhances the degradation of Bmal1 and Cbp, another circadian clock regulator, reducing binding of transcription factors to the Per2 promoter, and altering the oscillation of Per2 mRNA and protein expression in cell culture models and in the SCN of the 5×FAD transgenic mice model of AD [41]. …”

Mechanisms linking circadian clocks, sleep, and neurodegeneration

“…One post-mortem study demonstrated asynchronous clock gene expression between different brain regions in AD patients (50). Aβ can facilitate BMAL1 degradation in neuronal cells (51), suggesting that AD-related processes could directly influence cellular clock function. PD patients have blunted rhythms of clock gene expression in peripheral blood cells (52, 53), and transgenic mice overexpressing human alpha-synuclein, a neurodegenerative protein implicated in PD, develop behavioral and transcriptional circadian deficits (22).…”