Journal
JOURNAL OF ALZHEIMERS DISEASE
Volume 77, Issue 2, Pages 795-806Publisher
IOS PRESS
DOI: 10.3233/JAD-200331
Keywords
Alzheimer's disease; amyloid-beta; blood-cerebrospinal fluid barrier; choroid plexus; circadian clock; melatonin
Categories
Funding
- Health Sciences Research Center (CICS-UBI) through National Funds by FCT - Foundation for Science and Technology [UID/Multi/00709/2019]
- Programa Operacional do Centro, Centro 2020 through ICON project (Interdisciplinary Challenges on Neurodegeneration) [CENTRO-01-0145-FEDER-000013]
- German Federal Ministry of Education and Research (BMBF) [031A316]
- Dr. Rolf M. Schwiete Stiftung
- Berlin School of Integrative Oncology (BSIO)
- Instituto de Salud Carlos III [PI15/00780, PI18/00118]
- FEDER
- CIBERNED [PI2016/01]
- NEUROMETAB-CM from Comunidad de Madrid [S2017/BMD-3700]
- Structural Funds of the European Union
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Background: The choroid plexus (CP), which constitutes the blood-cerebrospinal fluid barrier, was recently identified as an important component of the circadian clock system. Objective: The fact that circadian rhythm disruption is closely associated to Alzheimer's disease (AD) led us to investigate whether AD pathology can contribute to disturbances of the circadian clock in the CP. Methods: For this purpose, we evaluated the expression of core-clock genes at different time points, in 6 and 12-month-old female and male APP/PS1 mouse models of AD. In addition, we also assessed the effect of melatonin pre-treatment in vitro before amyloid-beta stimulus in the daily pattern of brain and muscle Arnt-like protein 1 (Bmal1) expression. Results: Our results showed a dysregulation of circadian rhythmicity of Bmal1 expression in female and male APP/PS1 transgenic 12-month-old mice and of Period 2 (Per2) expression in male mice. In addition, a significant circadian pattern of Bmal1 was measured the intermittent melatonin pre-treatment group, showing that melatonin can reset the CP circadian clock. Conclusion: These results demonstrated a connection between AD and the disruption of circadian rhythm in the CP, representing an attractive target for disease prevention and/or treatment.
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