TY - JOUR
T1 - Regulation of amyloid-β dynamics and pathology by the circadian clock
AU - Kress, Geraldine J.
AU - Liao, Fan
AU - Dimitry, Julie
AU - Cedeno, Michelle R.
AU - FitzGerald, Garret A.
AU - Holtzman, David M.
AU - Musiek, Erik S.
N1 - Publisher Copyright:
© 2018 Kress et al.
PY - 2018/4/1
Y1 - 2018/4/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85043974638&partnerID=8YFLogxK
U2 - 10.1084/jem.20172347
DO - 10.1084/jem.20172347
M3 - Article
C2 - 29382695
AN - SCOPUS:85043974638
SN - 0022-1007
VL - 215
SP - 1059
EP - 1068
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 4
ER -