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Featured ArticleResearch Articles, Neurobiology of Disease

Disruption of Bmal1 Impairs Blood–Brain Barrier Integrity via Pericyte Dysfunction

Ryota Nakazato, Kenji Kawabe, Daisuke Yamada, Shinsuke Ikeno, Michihiro Mieda, Shigeki Shimba, Eiichi Hinoi, Yukio Yoneda and Takeshi Takarada
Journal of Neuroscience 18 October 2017, 37 (42) 10052-10062; DOI: https://doi.org/10.1523/JNEUROSCI.3639-16.2017
Ryota Nakazato
1Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa 920-1192, Japan,
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Kenji Kawabe
2Department of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan,
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Daisuke Yamada
2Department of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan,
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Shinsuke Ikeno
1Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa 920-1192, Japan,
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Michihiro Mieda
3Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan, and
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  • ORCID record for Michihiro Mieda
Shigeki Shimba
4Department of Health Science, College of Pharmacy, Nihon University, Chiba 274-8555, Japan
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Eiichi Hinoi
1Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa 920-1192, Japan,
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Yukio Yoneda
1Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa 920-1192, Japan,
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Takeshi Takarada
1Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa 920-1192, Japan,
2Department of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan,
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Abstract

Circadian rhythm disturbances are well established in neurological diseases. However, how these disruptions cause homeostatic imbalances remains poorly understood. Brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1) is a major circadian clock transcriptional activator, and Bmal1 deficiency in male Bmal1nestin−/− mice induced marked astroglial activation without affecting the number of astrocytes in the brain and spinal cord. Bmal1 deletion caused blood–brain barrier (BBB) hyperpermeability with an age-dependent loss of pericyte coverage of blood vessels in the brain. Using Nestin-green fluorescent protein (GFP) transgenic mice, we determined that pericytes are Nestin-GFP+ in the adult brain. Bmal1 deletion caused Nestin-GFP+ pericyte dysfunction, including the downregulation of platelet-derived growth factor receptor β (PDGFRβ), a protein necessary for maintaining BBB integrity. Knockdown of Bmal1 downregulated PDGFRβ transcription in the brain pericyte cell line. Thus, the circadian clock component Bmal1 maintains BBB integrity via regulating pericytes.

SIGNIFICANCE STATEMENT Circadian rhythm disturbances may play a role in neurodegenerative disorders, such as Alzheimer's disease. Our results revealed that one of the circadian clock components maintains the integrity of the blood–brain barrier (BBB) by regulating vascular-embedded pericytes. These cells were recently identified as a vital component for the control of BBB permeability and cerebral blood flow. Our present study demonstrates the involvement of circadian clock component Bmal1 in BBB homeostasis and highlights the role of Bmal1 dysfunction in multiple neurological diseases.

  • blood–brain barrier
  • Clock gene
  • pericyte
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The Journal of Neuroscience: 37 (42)
Journal of Neuroscience
Vol. 37, Issue 42
18 Oct 2017
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Disruption of Bmal1 Impairs Blood–Brain Barrier Integrity via Pericyte Dysfunction
Ryota Nakazato, Kenji Kawabe, Daisuke Yamada, Shinsuke Ikeno, Michihiro Mieda, Shigeki Shimba, Eiichi Hinoi, Yukio Yoneda, Takeshi Takarada
Journal of Neuroscience 18 October 2017, 37 (42) 10052-10062; DOI: 10.1523/JNEUROSCI.3639-16.2017

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Disruption of Bmal1 Impairs Blood–Brain Barrier Integrity via Pericyte Dysfunction
Ryota Nakazato, Kenji Kawabe, Daisuke Yamada, Shinsuke Ikeno, Michihiro Mieda, Shigeki Shimba, Eiichi Hinoi, Yukio Yoneda, Takeshi Takarada
Journal of Neuroscience 18 October 2017, 37 (42) 10052-10062; DOI: 10.1523/JNEUROSCI.3639-16.2017
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Keywords

  • blood–brain barrier
  • clock gene
  • pericyte

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