title: Circadian alterations during early stages of Alzheimer's disease are associated with aberrant cycles of DNA methylation in BMAL1.
abstract: BACKGROUND
  Circadian alterations are prevalent in Alzheimer's disease (AD) and may contribute to cognitive impairment, behavioral symptoms, and neurodegeneration. Epigenetic mechanisms regulate the circadian clock, and changes in DNA methylation have been reported in AD brains, but the pathways that mediate circadian deregulation in AD are incompletely understood. We hypothesized that aberrant DNA methylation may affect circadian rhythms in AD.
  
  
  METHODS
  We investigated DNA methylation, transcription, and expression of BMAL1, a positive regulator of the circadian clock, in cultured fibroblasts and brain samples from two independent cohorts of aging and AD.
  
  
  RESULTS
  DNA methylation modulated rhythmic expression of clock genes in cultured fibroblasts. Moreover, rhythmic methylation of BMAL1 was altered in AD brains and fibroblasts and correlated with transcription cycles.
  
  
  CONCLUSIONS
  Our results indicate that cycles of DNA methylation contribute to the regulation of BMAL1 rhythms in the brain. Hence, aberrant epigenetic patterns may be linked to circadian alterations in AD.
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Cronin
authors.affiliation: Psychiatry Service, Veterans Affairs San Diego Health Care System, San Diego, CA, USA; Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McCarthy
authors.affiliation: Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
authors.forename: Andrew S P
authors.initials: ASP
authors.lastname: Lim
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Salmon
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Galasko
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA; Department of Pathology, University of California San Diego, La Jolla, CA, USA.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.affiliation: Departments of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, USA; Department of Pathology, University of California San Diego, La Jolla, CA, USA. Electronic address: pdesplat@ucsd.edu.
authors.forename: Paula
authors.initials: P
authors.lastname: Desplats
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D019175:DNA Methylation; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005625:Frontal Lobe / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008297:Male; D014158:Transcription, Genetic
chemical_list: D056930:ARNTL Transcription Factors; C538960:BMAL1 protein, human
keywords: Alzheimer's disease; BMAL1; Brain; Circadian clock; Circadian rhythms; DNA methylation; Epigenetics; Fibroblasts; Methylation cycles; Neurodegeneration