Glymphatic dysfunction in the pathogenesis of neurodegenerative diseases and pathological aging

Abstract

Recently, the concept of the glymphatic system as a highly organized perivascular network has been formed, which by hydrodynamic approach, with the key participation of aquaporin-4 as a central molecule, connects the cerebrospinal fluid with the lymphatic vessels of the meninges through the brain interstitium. The latest scientific works demonstrates the potential role of glymphatic dysfunction in the development of neurodegeneration and pathological aging. Although the precise molecular mechanisms of glymphatic pathway function have not yet been fully characterized, the critical processes underlying cerebral solute transport and clearance of amyloid and metabolites have been largely elucidated. The complex interaction between a number of age-associated factors, including cellular aging, disturbances in the sleep-wake cycle with changes in sleep architecture and quality, low-grade systemic inflammation, and the development of concomitant diseases, determines not only life expectancy in general, but also forms the basis of healthy and unhealthy aging the brain in particular. Imbalances in homeostatic functions, changes in the activity of glymphatic clearance and the blood-brain barrier that support the exchange of fluid and solutes in cerebral tissue, which can be observed both normally with physiological aging and with the development of neuropathology, have longitudinal consequences ranging from disruption of synaptic signal transmission to onset of neurodegenerative processes.

This review analyzes the current scientific information in this area of research, details the features of the perivascular glial-mediated transport system, and discusses how its dysfunction plays a fundamental role in the pathological accumulation of metabolites during aging, the development of age-associated changes in the brain, and the progression of neurodegenerative diseases.

Keywords

glymphatic pathway, aquaporin-4, dysfunction, clearance, neurodegeneration, amyloid, blood-brain barrier

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