The “glymphatic” mechanism for solute clearance in Alzheimer's disease: game changer or unproven speculation?

Abstract

How solutes and macromolecules are removed from brain tissue is of central importance in normal brain physiology and in how toxic protein aggregates are cleared in neurodegenerative conditions, including Alzheimer's disease (AD). Conventionally, solute transport in the narrow and tortuous extracellular space in brain parenchyma has been thought to be primarily diffusive and nondirectional. The recently proposed "glymphatic" (glial-lymphatic) hypothesis posits that solute clearance is convective and driven by active fluid transport from para-arterial to paravenous spaces though aquaporin-4 water channels in astrocyte endfeet. Glymphatic, convective solute clearance has received much attention because of its broad implications for AD and other brain pathologies and even the function of sleep. However, the theoretical plausibility of glymphatic transport has been questioned, and recent data have challenged its experimental underpinnings. A substantiated mechanism of solute clearance in the brain is of considerable importance because of its implications for pathogenic mechanisms of neurologic diseases and delivery of therapeutics.-Smith, A. J., Verkman, A. S. The "glymphatic" mechanism for solute clearance in Alzheimer's disease: game changer or unproven speculation?

Paravascular spaces: entry to or exit from the brain?

“…However, it is important to note that several aspects of the glymphatic theory have been challenged by theoretical considerations and experimental studies (for reviews, see Abbott, Pizzo, Preston, Janigro, & Thorne, ; Hladky & Barrand, ; Smith & Verkman, ). In our view, the most important unresolved issues are as follows: (i) the direction, if any, of flow in the paravascular space of penetrating vessels; (ii) the physical basis for the pressure gradients that drive paravascular and ISF flow; (iii) the role of pressure pulsations; and (iv) the contribution of the water‐selective channel, AQ4, to solute transport.…”

“…However, it is important to note that several aspects of the glymphatic theory have been challenged by theoretical considerations and experimental studies (for reviews, see Abbott, Pizzo, Preston, Janigro, & Thorne, 2018;Hladky & Barrand, 2014;Smith & Verkman, 2018…”

Neuroendocrine-Metabolic Dysfunction and Sleep Disturbances in Neurodegenerative Disorders: Focus on Alzheimer’s Disease and Melatonin

“…Another aspect related to AD refers to the clearance of apolipoprotein E from the ECS, since sleep deprivation was found to suppress this process [50] as well as elimination of tau protein from ECS [51]. Although the glymphatic hypothesis remains a matter of controversy [52], the role of normal sleep for correct cerebral clearance of toxic products can be considered well established (Fig. 3).…”

Aquaporin‐4‐independent volume dynamics of astroglial endfeet during cortical spreading depression

“…It was originally proposed that interstitial waste products move by convective flow, both through the brain parenchyma and along the paravascular pathways (Iliff et al, ), possibly driven by arterial pulsations (Iliff et al, ). While recent evidence suggests that CSF movement through brain parenchyma occurs by diffusion, rather than by convection (Holter et al, ; Jin, Smith, & Verkman, ; Smith & Verkman, ; Smith, Yao, Dix, Jin, & Verkman, ), the convective nature of the paravascular flow has not been questioned (Abbott et al, ; Hladky & Barrand, ). Thus, the width of the paravascular space, interposed between the vascular tube and the glial endfoot sheath, must be a critical determinant of brain waste removal‐in acute conditions as well as in neurodegenerative diseases such as Alzheimer's disease.…”