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Regulation of amyloid-β dynamics and pathology by the circadian clock.

Authors
  • Kress, Geraldine J1, 2
  • Liao, Fan1
  • Dimitry, Julie1
  • Cedeno, Michelle R1
  • FitzGerald, Garret A3
  • Holtzman, David M1, 2, 4
  • Musiek, Erik S5, 2, 4
  • 1 Department of Neurology, Washington University School of Medicine, St. Louis, MO.
  • 2 Hope Center for Neurological Disease, Washington University School of Medicine, St. Louis, MO.
  • 3 Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
  • 4 Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO.
  • 5 Department of Neurology, Washington University School of Medicine, St. Louis, MO [email protected]
Type
Published Article
Journal
Journal of Experimental Medicine
Publisher
The Rockefeller University Press
Publication Date
Apr 02, 2018
Volume
215
Issue
4
Pages
1059–1068
Identifiers
DOI: 10.1084/jem.20172347
PMID: 29382695
Source
Medline
License
Unknown

Abstract

Nighttime restlessness and daytime drowsiness are common and early symptoms of Alzheimer's Disease (AD). This symptomology implicates dysfunctional biological timing, yet the role of the circadian system in AD pathogenesis is unknown. To evaluate the role of the circadian clock in amyloid-β (Aβ) dynamics and pathology, we used a mouse model of β-amyloidosis and disrupted circadian clock function either globally or locally in the brain via targeted deletion of the core clock gene Bmal1 Our results demonstrate that loss of central circadian rhythms leads to disruption of daily hippocampal interstitial fluid Aβ oscillations and accelerates amyloid plaque accumulation, whereas loss of peripheral Bmal1 in the brain parenchyma increases expression of Apoe and promotes fibrillar plaque deposition. These results provide evidence that both central circadian rhythms and local clock function influence Aβ dynamics and plaque formation and demonstrate mechanisms by which poor circadian hygiene may directly influence AD pathogenesis.

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