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Nature. 2018 Aug;560(7717):185-191. doi: 10.1038/s41586-018-0368-8. Epub 2018 Jul 25.

Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease.

Author information

1
Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA. sd8tf@virginia.edu.
2
Department of Neuroscience, University of Virginia, Charlottesville, VA, USA. sd8tf@virginia.edu.
3
Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA.
4
Department of Neuroscience, University of Virginia, Charlottesville, VA, USA.
5
Virginia Image and Video Analysis Laboratory, Department of Electrical and Computer Engineering, University of Virginia, Charlottesville, VA, USA.
6
Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.
7
Department of Mathematics, University of Trento, Povo, Italy.
8
Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
9
Department of Neurosurgery, University of Virginia Health System, Charlottesville, VA, USA.
10
Department of Biomedical Engineering and Mechanics, College of Engineering, Virginia Tech, Blacksburg, VA, USA.
11
Department of Pathology, University of Virginia, Charlottesville, VA, USA.
12
Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA. kipnis@virginia.edu.
13
Department of Neuroscience, University of Virginia, Charlottesville, VA, USA. kipnis@virginia.edu.

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.

PMID:
30046111
PMCID:
PMC6085146
DOI:
10.1038/s41586-018-0368-8
[Indexed for MEDLINE]
Free PMC Article

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