Functional abnormalities of the glymphatic system in cognitive disorders

Abstract

Various pathological mechanisms represent distinct therapeutic targets for cognitive disorders, but a balance between clearance and production is essential for maintaining the stability of the brain's internal environment. Thus, the glymphatic system may represent a common pathway by which to address cognitive disorders. Using the established model of the glymphatic system as our foundation, this review disentangles and analyzes the components of its clearance mechanism, including the initial inflow of cerebrospinal fluid, the mixing of cerebrospinal fluid with interstitial fluid, and the outflow of the mixed fluid and the clearance. Each section summarizes evidence from experimental animal models and human studies, highlighting the normal physiological properties of key structures alongside their pathological manifestations in cognitive disorders. The same pathologic manifestations of different cognitive disorders appearing in the glymphatic system and the same upstream influences are main points of interest of this review. We conclude this article by discussing new findings and outlining the limitations identified in current research progress.

Figure 1

Comparison of healthy and cognitive disorder–affected brain glymphatic function. The image contrasts the glymphatic system of a healthy brain with that of a brain affected by cognitive impairment. In a healthy brain, strong arterial pulsation is the main driving force for cerebrospinal fluid influx. Healthy astrocytes and polarized AQP4 clear waste from the brain parenchyma. In contrast, the brain affected by cognitive impairment experiences impaired meningeal lymphatic drainage, reduced arterial pulsation, insufficient cerebrospinal fluid driving force, expanded perivascular spaces, pathological changes in astrocytes, and loss of AQP4 polarization. This ultimately leads to the accumulation of waste, including amyloid proteins. This figure highlights the critical role of the glymphatic system in maintaining brain health and its implications for cognitive disorders. AQP4: Aquaporin-4.

Figure 2

Components of the glymphatic system. This image summarizes the components of the glymphatic system: Pathways of CSF into the brain parenchyma (A), clearing within the brain parenchyma (B), and outflow and clearance of CSF–ISF mixture (C). CSF: Cerebrospinal fluid; ISF: interstitial fluid.

Figure 3

Pathologic changes in astrocytes in cognitive disorders. The image includes labels for end-foot degeneration, proliferation, hypertrophy, protein deposition, senescent astrocytes, reactive astrocytes, and healthy astrocytes. These labels illustrate the diverse pathological alterations of aquaporin-4 in different cognitive disorders, highlighting their impact on the glymphatic system.

Figure 4

Expression properties and microstructure of AQP4 in the glymphatic system. (A) AQP4 is predominantly expressed on cell membranes at the junction between brain parenchyma and brain fluid components, this property is also known as polarization. (B) AQP4 on astrocyte endfeet is co-constitutive with internal rectifier potassium ion (potassium phosphate ion channel) channels to form OAPs. (C) Four AQP4 monomers make up the AQP4 protein. AQP4: Aquaporin-4.

Figure 5

Clearance in the brain parenchyma. If we analogize cerebrospinal fluid to a marching crowd, then what happens after entering the brain substance can be described as a crowd that was walking on a flat road, entering a wooded and muddy jungle, and moving forward together through the forest after meeting up with their heavily loaded companions.

Figure 6

Two types of outflow models for the cerebrospinal fluid–interstitial fluid mixture. (A) The most widely accepted glymphatic pathway mirrors the inflow route, entering the cerebrospinal fluid circulation through the perivascular space behind the capillaries. (B) In the IPAD model, both outflow and inflow pathways are peri-arterial vascular spaces and have pathological protein deposits. IPAD: Intramural periarterial drainage.