Reviewing Waste Clearance in the Brain via the Glymphatic System

Clearance of metabolic waste from the brain via fluid drainage pathways is becoming an important topic in the context of age-related neurodegeneration, as is noted by the authors of this open access review paper. There is good evidence to suggest that drainage of cerebrospinal fluid is a significant path for the removal of wastes, such as the protein aggregates associated with dementia, and that the relevant fluid channels atrophy and fail with age. That decline may well be an important contribution to the development of neurodegenerative disease in later life, and the first efforts to do something about it are now underway. Restoring drainage is the goal of Leucadia Therapeutics, for example, a company that will probably be joined by similar initiatives in the years ahead.

Waste removal from the central nervous system is essential for maintaining brain homeostasis across the lifespan. Two interconnected, dynamic networks were recently uncovered, which may provide new information concerning the conundrum of how the brain manages waste removal in the absence of authentic lymphatic vessels (LVs). The glymphatic system serves as the brain’s “front end” waste drainage pathway that includes a perivascular network for cerebrospinal fluid (CSF) transport, which is connected to a downstream authentic lymphatic network associated with the meninges, cranial nerves, and large vessels exiting the skull. The anatomical and functional components of the two systems are complex, and the processes by which they physically interconnect are only partly understood.

The first pioneering studies documented that soluble amyloid beta (Aβ) protein and tau oligomers – metabolic waste products whose buildup is associated with Alzheimer’s disease (AD) – were transported from the interstitial fluid (ISF) space and out of the brain via the glymphatic system. This information was followed by another hallmark study reporting that slow wave sleep enhanced glymphatic Aβ clearance from brain when compared to wakefulness. Collectively, this information was met with excitement in the neuroscience and clinical communities because maintaining efficient brain waste drainage across the lifespan – possibly by preserving normal sleep architecture – emerged as a novel therapeutic target for preventing cognitive dysfunction and decline.

The idea of maximizing brain “waste drainage” as a new preventive or therapeutic target for neurodegenerative disease states was further strengthened by animal studies providing evidence of declining glymphatic transport efficiency in healthy aging, AD models, traumatic brain injury, cerebral hemorrhage, and stroke. Considering the novelty of the glymphatic system concept, along with the rapidly emerging literature associating key physiological processes (e.g., vascular pulsatility, and sleep) with glymphatic transport function and waste solute outflow from brain, we decided it was timely to review this information cohesively. Hence, the goal of this mini-review is to provide a broad overview of the current data, controversies, and gaps in knowledge of the glymphatic system and waste drainage from the brain, while addressing potential consequences of aging as well as critically reviewing evidence for its existence in the human brain.


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