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

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)10052-10062
Number of pages11
JournalJournal of Neuroscience
Volume37
Issue number42
DOIs
Publication statusPublished - Oct 18 2017

Fingerprint

Pericytes
Blood-Brain Barrier
Nestin
Green Fluorescent Proteins
Brain
Platelet-Derived Growth Factor Receptors
Circadian Clocks
ARNTL Transcription Factors
Down-Regulation
Circadian Rhythm
Astrocytes
Transgenic Mice
Blood Vessels
Spinal Cord
Cell Line
Muscles
Proteins

Keywords

  • Blood-brain barrier
  • Clock gene
  • Pericyte

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Disruption of Bmal1 impairs blood-brain barrier integrity via pericyte dysfunction. / Nakazato, Ryota; Kawabe, Kenji; Yamada, Daisuke; Ikeno, Shinsuke; Mieda, Michihiro; Shimba, Shigeki; Hinoi, Eiichi; Yoneda, Yukio; Takarada, Takeshi.

In: Journal of Neuroscience, Vol. 37, No. 42, 18.10.2017, p. 10052-10062.

Research output: Contribution to journalArticle

Nakazato, R, Kawabe, K, Yamada, D, Ikeno, S, Mieda, M, Shimba, S, Hinoi, E, Yoneda, Y & Takarada, T 2017, 'Disruption of Bmal1 impairs blood-brain barrier integrity via pericyte dysfunction', Journal of Neuroscience, vol. 37, no. 42, pp. 10052-10062. https://doi.org/10.1523/JNEUROSCI.3639-16.2017
Nakazato, Ryota ; Kawabe, Kenji ; Yamada, Daisuke ; Ikeno, Shinsuke ; Mieda, Michihiro ; Shimba, Shigeki ; Hinoi, Eiichi ; Yoneda, Yukio ; Takarada, Takeshi. / Disruption of Bmal1 impairs blood-brain barrier integrity via pericyte dysfunction. In: Journal of Neuroscience. 2017 ; Vol. 37, No. 42. pp. 10052-10062.
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