title: Aβ-induced degradation of BMAL1 and CBP leads to circadian rhythm disruption in Alzheimer's disease.
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.
authors.affiliation: Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, 103 Daehak-ro, Seoul, 110-799, Jongno-gu, Korea. eternalshd@snu.ac.kr.
authors.forename: Hyundong
authors.initials: H
authors.lastname: Song
authors.affiliation: Department of Biochemistry, College of Medicine, Konyang University, Daejeon, 302-718, Korea. hominmoon@hanmail.net.
authors.forename: Minho
authors.initials: M
authors.lastname: Moon
authors.affiliation: Department of Biological Sciences, Seoul National University, Seoul, 151-742, Korea. inc67@snu.ac.kr.
authors.forename: Han Kyoung
authors.initials: HK
authors.lastname: Choe
authors.affiliation: Department of Neuroscience and Neurodegeneration Control Research Center, Kyung Hee University, Seoul, 130-701, Korea. neodoit@hanmail.net.
authors.forename: Dong-Hee
authors.initials: DH
authors.lastname: Han
authors.affiliation: Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, 103 Daehak-ro, Seoul, 110-799, Jongno-gu, Korea. chjang70@snu.ac.kr.
authors.forename: Changhwan
authors.initials: C
authors.lastname: Jang
authors.affiliation: Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, 103 Daehak-ro, Seoul, 110-799, Jongno-gu, Korea. dkqls0207@gmail.com.
authors.forename: Ahbin
authors.initials: A
authors.lastname: Kim
authors.affiliation: Department of Neuroscience and Neurodegeneration Control Research Center, Kyung Hee University, Seoul, 130-701, Korea. sehyung@khu.ac.kr.
authors.forename: Sehyung
authors.initials: S
authors.lastname: Cho
authors.affiliation: Department of Brain Science, DGIST, Daegu, 711-873, Korea. kyungjin@snu.ac.kr.
authors.forename: Kyungjin
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, 103 Daehak-ro, Seoul, 110-799, Jongno-gu, Korea. inhee@snu.ac.kr.
authors.forename: Inhee
authors.initials: I
authors.lastname: Mook-Jung
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000544:Alzheimer Disease / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000235:genetics*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008822:Mice, Transgenic; D056950:Period Circadian Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D056930:ARNTL Transcription Factors; D016229:Amyloid beta-Peptides; C538961:Bmal1 protein, mouse; D008565:Membrane Proteins; C498709:Pag1 protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D010750:Phosphoproteins; D014157:Transcription Factors