Glymphatics

• The glymphatic system is a highly polarized macroscopic system of convective fluid fluxes that facilitates the rapid interchange between cerebrospinal fluid (CSF) and interstitial fluid (ISF).

• Periarterial Influx:
• The system utilizes a unique network of perivascular channels (also known as the Virchow-Robin space).
• From the subarachnoid space, CSF is driven along these channels, specifically surrounding the pial arteries and penetrating arterioles.
• The loose fibrous matrix of this space provides a low-resistance pathway for CSF influx.

• Astrocytic Regulation:
• The perivascular channels are formed and bordered by astroglial cells.
• Specifically, the astrocytic vascular endfeet surround the vasculature.

• Parenchymal Flow:
• CSF transport into the dense brain parenchyma is facilitated by the aquaporin-4 (AQP4) water channels.
• AQP4 is expressed in a highly polarized manner in the astrocytic endfeet that ensheathe the brain vasculature.
• Studies using AQP4 knockout mice showed a dramatic reduction (approximately 65%) in CSF fluid flux through the parenchyma.

• Perivenous Efflux:
• The convective CSF movement through the brain tissue drives interstitial fluid fluxes toward the perivenous spaces.
• From these perivenous spaces surrounding the large deep veins, the fluid (now containing collected interstitial solutes) drains out of the brain toward the cervical lymphatic system.

• Paravascular spaces forming pathways

Vessel type	Artery	Arterioles/capillaries/venules	Veins
Paravascular space	Virchow-robin spaces	Basal lamina's extracellular matrix	Perivenous spaces

• Virchow-robin spaces
• Perivascular spaces around penetrating arteries
• They disappear when arteries become arterioles

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• Aging:
• Glymphatic activity declines sharply (by approximately 80-90%) in aged mice.
• This failure is potentially attributable to the
• Loss of AQP4 polarization in reactive astrocytes
• A decline in arterial pulsatility
• The age-related decline may contribute to the accumulation of misfolded proteins, which is a major risk factor for neurodegenerative diseases.

• Neurodegenerative Disorders:
• Failure of glymphatic function might contribute to pathology in neurodegenerative disorders, including Alzheimer's disease.
• Accumulation of β-amyloid around cerebral arteries is consistent with the anatomical routes of bulk flow.