期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 215, 期 4, 页码 1059-1068出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20172347
关键词
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资金
- Hope Center Surgery and Viral Vector Cores at Washington University in St. Louis
- Washington University in St. Louis Center for Cellular Imaging
- National Institute on Aging [K01AG053425]
- National Institute on Neurological Disorders and Stroke [K08NS079405, P01NS074969]
- Alzheimer's Association New Investigator Research Grant
- Donors Cure Foundation
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-beta (A beta) dynamics and pathology, we used a mouse model of beta-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 A beta 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 A beta dynamics and plaque formation and demonstrate mechanisms by which poor circadian hygiene may directly influence AD pathogenesis.
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