Functional Aspects of Meningeal Lymphatics in Ageing and Alzheimer's Disease

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging / cerebrospinal fluid*
  • Aging / pathology
  • Alzheimer Disease / cerebrospinal fluid*
  • Alzheimer Disease / pathology
  • Alzheimer Disease / physiopathology*
  • Amyloid / metabolism
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Brain / metabolism
  • Cognition
  • Cognition Disorders / physiopathology
  • Cognition Disorders / therapy
  • Disease Models, Animal
  • Extracellular Fluid / metabolism
  • Female
  • Homeostasis
  • Humans
  • Lymph Nodes / metabolism
  • Lymphatic Vessels / pathology
  • Lymphatic Vessels / physiopathology*
  • Male
  • Meninges / pathology
  • Meninges / physiopathology*
  • Mice
  • Mice, Transgenic
  • Perfusion

Substances

  • Amyloid
  • Amyloid beta-Peptides