A control mechanism for intra-mural peri-arterial drainage via astrocytes: How neuronal activity could improve waste clearance from the brain

PLoS One. 2018 Oct 4;13(10):e0205276. doi: 10.1371/journal.pone.0205276. eCollection 2018.

Abstract

The mechanisms behind the clearance of soluble waste from deep within the parenchyma of the brain remain unclear. Experimental evidence reveals that one pathway for clearance of waste, termed intra-mural peri-arterial drainage (IPAD), is the rapid drainage of interstitial fluid along basement membranes (BM) of the smooth muscle cells of cerebral arteries; failure of IPAD is closely associated with the pathology of Alzheimer's disease (AD), but its driving mechanism remains unclear. We have previously shown that arterial pulsations generated by the heart beat are not strong enough to drive IPAD. Here we present computational evidence for a mechanism for clearance of waste from the brain that is driven by functional hyperaemia, that is, the dilatation of cerebral arterioles as a consequence of increased nutrient demand from neurons. This mechanism is based on our model for the flow of fluid through the vascular BM. It accounts for clearance rates observed in mouse experiments, and aligns with pathological observations and recommendations to lower the individual risk of AD, such as mental and physical activity. Thus, our neurovascular hypothesis should act as the new working hypothesis for the driving force behind IPAD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / pathology
  • Alzheimer Disease / therapy*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Brain / metabolism
  • Brain / pathology*
  • Capillaries / metabolism
  • Capillaries / pathology
  • Cerebral Amyloid Angiopathy*
  • Cerebral Arteries / metabolism
  • Cerebral Arteries / pathology
  • Drainage / methods*
  • Extracellular Fluid / metabolism
  • Humans
  • Mice
  • Myocytes, Smooth Muscle / metabolism
  • Myocytes, Smooth Muscle / pathology
  • Neurons

Substances

  • Amyloid beta-Peptides

Grant support

This research was funded by the UK Engineering and Physical Sciences Research Council (EPSRC) grant number EP/N509747/1 (AKD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.