Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease

Sandro Mesquita (), Antoine Louveau, Andrea Vaccari, Igor Smirnov, R. Chase Cornelison, Kathryn M. Kingsmore, Christian Contarino, Suna Onengut-Gumuscu, Emily Farber, Daniel Raper, Kenneth E. Viar, Romie D. Powell, Wendy Baker, Nisha Dabhi, Robin Bai, Rui Cao, Song Hu, Stephen S. Rich, Jennifer M. Munson, M. Beatriz Lopes, Christopher C. Overall, Scott T. Acton and Jonathan Kipnis ()
Additional contact information
Sandro Mesquita: University of Virginia
Antoine Louveau: University of Virginia
Andrea Vaccari: University of Virginia
Igor Smirnov: University of Virginia
R. Chase Cornelison: University of Virginia
Kathryn M. Kingsmore: University of Virginia
Christian Contarino: University of Virginia
Suna Onengut-Gumuscu: Center for Public Health Genomics, University of Virginia
Emily Farber: Center for Public Health Genomics, University of Virginia
Daniel Raper: University of Virginia
Kenneth E. Viar: University of Virginia
Romie D. Powell: University of Virginia
Wendy Baker: University of Virginia
Nisha Dabhi: University of Virginia
Robin Bai: University of Virginia
Rui Cao: University of Virginia
Song Hu: University of Virginia
Stephen S. Rich: Center for Public Health Genomics, University of Virginia
Jennifer M. Munson: University of Virginia
M. Beatriz Lopes: University of Virginia
Christopher C. Overall: University of Virginia
Scott T. Acton: University of Virginia
Jonathan Kipnis: University of Virginia

Nature, 2018, vol. 560, issue 7717, 185-191

Abstract: Abstract Ageing is a major risk factor for many neurological pathologies, but its mechanisms remain unclear. Unlike other tissues, the parenchyma of the central nervous system (CNS) lacks lymphatic vasculature and waste products are removed partly through a paravascular route. (Re)discovery and characterization of meningeal lymphatic vessels has prompted an assessment of their role in waste clearance from the CNS. Here we show that meningeal lymphatic vessels drain macromolecules from the CNS (cerebrospinal and interstitial fluids) into the cervical lymph nodes in mice. Impairment of meningeal lymphatic function slows paravascular influx of macromolecules into the brain and efflux of macromolecules from the interstitial fluid, and induces cognitive impairment in mice. Treatment of aged mice with vascular endothelial growth factor C enhances meningeal lymphatic drainage of macromolecules from the cerebrospinal fluid, improving brain perfusion and learning and memory performance. Disruption of meningeal lymphatic vessels in transgenic mouse models of Alzheimer’s disease promotes amyloid-β deposition in the meninges, which resembles human meningeal pathology, and aggravates parenchymal amyloid-β accumulation. Meningeal lymphatic dysfunction may be an aggravating factor in Alzheimer’s disease pathology and in age-associated cognitive decline. Thus, augmentation of meningeal lymphatic function might be a promising therapeutic target for preventing or delaying age-associated neurological diseases.

Keywords: Meningeal Lymphatic Vessels; Lnσ Dc; Lymphatic Ablation; Visudyne; 5XFAD Mice (search for similar items in EconPapers)
Date: 2018
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DOI: 10.1038/s41586-018-0368-8

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