Glymphatic dysfunction in the pathogenesis of neurodegenerative diseases and pathological aging

Abstract

The complex interaction between a number of age-related factors, including cellular aging, impair of the sleep-wake cycle and architecture and/or quality of sleep, inflammaging, and the development of comorbidities, determines not only life expectancy in general, but also forms the basis of healthy and unhealthy ageing in particular. An imbalance in the homeostatic functions that support the exchange of fluid and solutes in the cerebral tissue, which can be observed both in normal physiological ageing and in the development of neuropathology, has longitudinal consequences ranging from impaired synaptic signaling to the onset of neurodegenerative diseases. Recently, the concept of the Glymphatic system as a highly organized perivascular pathway has been formed, which connects the cerebrospinal fluid with the lymphatic vessels of the meninges through the brain tissue. Although the precise molecular mechanisms of the glymphatic pathway have not yet been completely characterized, the key processes underlying solute transport and metabolite clearance have already been substantially identified. This review analyzes current scientific information in this area of research, describes in detail the features of the perivascular glial-dependent clearance system, and discusses that its dysfunction assumes fundamental importance in the pathological accumulation of metabolites during ageing, the development of age-related changes in the brain, and the progression of neurodegenerative diseases.