The Rhythmicity of Clock Genes is Disrupted in the Choroid Plexus of the APP/PS1 Mouse Model of Alzheimer’s Disease

Article type: Research Article

Authors: Furtado, André^a | Astaburuaga, Rosario^{b; c} | Costa, Ana^a | Duarte, Ana C.^a | Gonçalves, Isabel^a | Cipolla-Neto, José^d | Lemos, Manuel C.^a | Carro, Eva^{e; f} | Relógio, Angela^{b; c; g} | Santos, Cecília R.A.^{a; 1} | Quintela, Telma^{a; 1; *}

Affiliations: [a] CICS-UBI - Health Sciences Research Center, University of Beira Interior, Covilhã, Portugal | [b] Institute for Theoretical Biology (ITB), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt - Universität zu Berlin, Berlin Institute of Health, Germany | [c] Medical Department of Hematology, Oncology, and Tumor Immunology and Molekulares Krebsforschungszentrum (MKFZ), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt - Universität zu Berlin, Berlin Institute of Health, Germany | [d] Laboratory of Neurobiology, Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil | [e] Networked Biomedical Research Center in Neurodegenerative Diseases (CIBERNED), Spain | [f] Group of Neurodegenerative Diseases, Hospital 12 de Octubre Research Institute (imas12), Madrid, Spain | [g] Department of Human Medicine, Institute for Systems Medicine and Bioinformatics, MSH Medical School Hamburg – University of Applied Sciences and Medical University, Hamburg, Germany

Correspondence: [*] Correspondence to: Telma Quintela. Health Sciences Research Center (CICS-UBI), Av. Infante D. Henrique, 6200-506 Covilhã, Portugal. Tel.: +351 275 329 002/3; E-mail: tquintela@fcsaude.ubi.pt.

Note: [1] These authors share senior authorship.

Abstract: 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-β 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.

Keywords: Alzheimer’s disease, amyloid-β, blood-cerebrospinal fluid barrier, choroid plexus, circadian clock, melatonin

DOI: 10.3233/JAD-200331

Journal: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 795-806, 2020