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

Peter Cronin; Michael J McCarthy; Andrew S P Lim; David P Salmon; Douglas Galasko; Eliezer Masliah; Philip L De Jager; David A Bennett; Paula Desplats

doi:10.1016/j.jalz.2016.10.003

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

Alzheimers Dement. 2017 Jun;13(6):689-700. doi: 10.1016/j.jalz.2016.10.003. Epub 2016 Nov 22.

Authors

Peter Cronin¹, Michael J McCarthy², Andrew S P Lim³, David P Salmon¹, Douglas Galasko¹, Eliezer Masliah⁴, Philip L De Jager⁵, David A Bennett⁶, Paula Desplats⁷

Affiliations

¹ Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
² 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.
³ Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
⁴ Department of Neurosciences, University of California San Diego, La Jolla, CA, USA; Department of Pathology, University of California San Diego, La Jolla, CA, USA.
⁵ Departments of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, USA.
⁶ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
⁷ 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.

Abstract

Introduction: 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.

Discussion: 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.

Keywords: Alzheimer's disease; BMAL1; Brain; Circadian clock; Circadian rhythms; DNA methylation; Epigenetics; Fibroblasts; Methylation cycles; Neurodegeneration.

MeSH terms

ARNTL Transcription Factors / genetics
ARNTL Transcription Factors / metabolism*
Aged, 80 and over
Alzheimer Disease / genetics
Alzheimer Disease / metabolism*
Case-Control Studies
Cells, Cultured
Circadian Rhythm / genetics
Circadian Rhythm / physiology*
DNA Methylation*
Female
Fibroblasts / metabolism
Frontal Lobe / metabolism
Gene Expression
Humans
Male
Transcription, Genetic

Substances

ARNTL Transcription Factors
BMAL1 protein, human

Abstract

MeSH terms

Substances

Grants and funding