Sleep, Glymphatic Flow and Proteostasis: Linking Sleep Physiology to Neurodegenerative Risk

Abstract

Sleep is essential for maintaining brain health, cognitive performance, and neurological function. Recently, increasing scientific attention has been directed toward understanding the physiological mechanisms through which sleep exerts its restorative effects. The discovery of the glymphatic system (GS) offers a new conceptual approach to understanding how the brain eliminates metabolic waste and neurotoxic aggregates. During sleep, GS facilitates the convective exchange of cerebrospinal and interstitial fluids to remove harmful byproducts. These processes are linked to proteostasis, the regulation of protein synthesis, folding, and degradation, which ensures cellular homeostasis and prevents the accumulation of misfolded proteins. Dysfunction of glymphatic flow or proteostasis is a key contributor to the onset and progression of neurodegenerative diseases. Research findings from studies demonstrate that poor sleep quality and short sleep duration produce decreased glymphatic clearance of debris, contributing to protein aggregation and cellular die-off and injury. Conversely, restorative sleep impairs waste flushing while protecting neural function. The present review provided recent research about the interplay of sleep physiology, glymphatic flow, and proteostasis to provide an understanding of these three interrelated processes simultaneously in the context of risk of neurodegenerative disease. It also includes emerging treatment approaches such as sleep optimization, pharmacological modulation of glymphatic flow, and enhancement of the proteostasis pathways that may avoid age-related cognitive decline that ultimately plays a role in brain health across the lifespan.

Keywords: Sleep, Glymphatic System, Proteostasis, Neurodegeneration