Piezol agonist restores meningeal lymphatic vessels, drainage, and brain-CSF perfusion in craniosynostosis and aged mice

Skull development coincides with the onset of cerebrospinal fluid (CSF) circulation, brain-CSF perfusion, and meningeal lymphangiogenesis, processes essential for brain waste clearance. How these processes are affected by craniofacial disorders such as craniosynostosis are poorly understood. We repo...

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Bibliographic Details
Published in:The Journal of clinical investigation 2024-02, Vol.134 (4)
Main Authors: Matrongolo, Matt J, Ang, Phillip S, Wu, Junbing, Jain, Aditya, Thackray, Joshua K, Reddy, Akash, Sung, Chi Chang, Barbe, Gaetan, Hong, Young-Kwon, Tischfield, Max A
Format: Article
Language:English
Subjects:
Alzheimer's disease
Brain research
Cerebrospinal fluid
Complications and side effects
Craniosynostoses
Drug therapy
Genetic engineering
Health aspects
Ion channels
Meninges
Physiological aspects
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Summary:Skull development coincides with the onset of cerebrospinal fluid (CSF) circulation, brain-CSF perfusion, and meningeal lymphangiogenesis, processes essential for brain waste clearance. How these processes are affected by craniofacial disorders such as craniosynostosis are poorly understood. We report that raised intracranial pressure and diminished CSF flow in craniosynostosis mouse models associate with pathological changes to meningeal lymphatic vessels that affect their sprouting, expansion, and long-term maintenance. We also show that craniosynostosis affects CSF circulatory pathways and perfusion into the brain. Further, craniosynostosis exacerbates amyloid pathology and plaque buildup in [Twist1.sup.+/-] :5xFAD transgenic Alzheimer's disease models. Treating craniosynostosis mice with Yoda1, a small molecule agonist for Piezo1, reduces intracranial pressure and improves CSF flow, in addition to restoring meningeal lymphangiogenesis, drainage to the deep cervical lymph nodes, and brain-CSF perfusion. Leveraging these findings, we show that Yoda1 treatments in aged mice with reduced CSF flow and turnover improve lymphatic networks, drainage, and brain-CSF perfusion. Our results suggest that CSF provides mechanical force to facilitate meningeal lymphatic growth and maintenance. Additionally, applying Yoda1 agonist in conditions with raised intracranial pressure and/or diminished CSF flow, as seen in craniosynostosis or with ageing, is a possible therapeutic option to help restore meningeal lymphatic networks and brain-CSF perfusion.
ISSN:0021-9738
DOI:10.1172/JCI171468