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

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

Research output: Contribution to journalArticlepeer-review

121 Scopus citations

Abstract

Background: 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. Results: In 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. Conclusions: Our results elucidate the underlying mechanisms for disrupted circadian rhythm in AD.

Original languageEnglish
Article number13
JournalMolecular Neurodegeneration
Volume10
Issue number1
DOIs
StatePublished - 19 Mar 2015

Bibliographical note

Publisher Copyright:
© 2015 Song et al.; licensee BioMed Central.

Keywords

  • Alzheimer's disease (AD)
  • Amyloid-beta (Aβ)
  • BMAL1 (Aryl hydrocarbon receptor nuclear translocator-like)
  • CBP (Creb-binding protein)
  • Circadian rhythm

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