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

Sep 16, 2017The Journal of neuroscience : the official journal of the Society for Neuroscience

Disrupting Bmal1 Weakens the Blood-Brain Barrier by Affecting Support Cells

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Abstract

Bmal1 deficiency in male mice induced marked astroglial activation and blood-brain barrier (BBB) hyperpermeability.

Bmal1 is a crucial factor in regulating the circadian rhythm and is associated with maintaining BBB integrity.
Astroglial activation occurred without a change in the total number of astrocytes in the brain and spinal cord following Bmal1 deletion.
An age-dependent loss of pericyte coverage of blood vessels was observed in the brains of Bmal1-deficient mice.
Bmal1 deletion resulted in dysfunction of Nestin-GFP pericytes, including a decrease in the protein necessary for BBB integrity.
Downregulation of platelet-derived growth factor receptor β (PDGFRβ) was linked to Bmal1 knockdown in a pericyte cell line.

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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 malemice 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-GFPin the adult brain. Bmal1 deletion caused Nestin-GFPpericyte 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.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. Bmal1nestin -/-+ + SIGNIFICANCE STATEMENT

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

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