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

Alexandra K Diem,Neil W Bressloff,Roy O Weller,Roxana O Carare,Mária A Deli

doi:10.1371/journal.pone.0205276

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.

Highlights

The brain lacks traditional lymphatics and until now the driving mechanisms behind the clearance of soluble waste from the brain have remained largely unclear
Pathological evidence suggests the presence of a pathway for the clearance of soluble waste along the basement membranes (BM) of smooth muscle cells (SMC) within artery walls, termed intramural periarterial drainage (IPAD)
We successfully demonstrate the clearance of waste metabolites from the brain at a rate comparable to experimental observations by [1] by combining our model of flow through the BM by [9] with a finite element (FE) model of the artery wall of an arteriole

Summary

Introduction

The brain lacks traditional lymphatics and until now the driving mechanisms behind the clearance of soluble waste from the brain have remained largely unclear. The pathway of IPAD was first described by Carare et al [1] and is one of two major hypotheses on the mechanism behind the clearance of soluble waste from the brain.

Results

Conclusion