Current Understanding of Central Nervous System Drainage Systems: Implications in the Context of Neurodegenerative Diseases

Abstract

: Until recently, it was thought that there were no lymphatic vessels in the central nervous system (CNS). Therefore, all metabolic processes were assumed to take place only in the circulation of the cerebrospinal fluid (CSF) and through the blood-brain barrier’s (BBB), which regulate ion transport and ensure the functioning of the CNS. However, recent findings yield a new perspective: There is an exchange of CSF with interstitial fluid (ISF), which is drained to the paravenous space and reaches lymphatic nodes at the end. This circulation is known as the glymphatic system. The glymphatic system is an extensive network of meningeal lymphatic vessels (MLV) in the basal area of the skull that provides another path for waste products from CNS to reach the bloodstream. MLV develop postnatally, initially appearing around the foramina in the basal part of the skull and the spinal cord, thereafter sprouting along the skull’s blood vessels and spinal nerves in various areas of the meninges. VEGF-C protein (vascular endothelial growth factor), expressed mainly by vascular smooth cells, plays an important role in the development of the MLV. The regenerative potential and plasticity of MLV and the novel discoveries related to CNS drainage offer potential for the treatment of neurodegenerative diseases such as dementia, hydrocephalus, stroke, multiple sclerosis, and Alzheimer disease (AD). Herein, we present an overview of the structure and function of the glymphatic system and MLV, and their potential involvement in the pathology and progression of neurodegenerative diseases.

The Interstitial System of the Brain in Health and Disease

“…Simple diffusion delivery (SDD) is another local brain drug delivery method that utilizes the concentration gradients to drive pharmaceutical agents to target zones via the brain ISS [135]. Since the brain ISS is divided into different segments based on brain ISF drainage [88,92,118,135], SDD has promise for delivering drugs to specific regions of the brain. However, before targeting drugs to brain regions through an SDD method, the tracerbased MRI technique may need to be used to ensure the brain ISF drainage in the area of the brain where the drug needs to be targeted.…”

“…It is believed that blockage of brain ISF drainage accelerates the abnormal deposition of betaamyloid in AD, which contributes to both cerebral amyloid angiopathy and neurodegeneration [23,114,115]. Changes in the ISS have also been reported in other diseases, such as Parkinson's disease [116], multiple sclerosis [117,118], and epilepsy [17,119]. Moreover, another study in a mouse model of AD by Yue and associates suggested that the destruction of beta-amyloid deposits in the ECS using a light-emitting diode with red light facilitated not only the recovery of ISF drainage but also rescued cognitive function [15].…”

Beneficial effects of voluntary exercise therapy on an Alzheimer’s mouse model are dependent on aquaporin 4-mediated glymphatic transport

“…Increasing evidence supports the idea that the glymphatic system plays a central role in the clearance of macromolecular substances from the brain [22,23]. This model of glymphatic system has opened up new perspectives in understanding the pathogenesis of AD [49,50], stroke [51,52], brain injury [53] and other neurological diseases [54,55]. Glymphatic system visualization is not only implemented in animal studies [56,57], but also being used for clinical imaging diagnosis of hydrocephalus [58,59] and AD [60].…”

Amygdala: Neuroanatomical and Morphophysiological Features in Terms of Neurological and Neurodegenerative Diseases

“…Neurodegenerative diseases are often associated with age [70]. Throughout life, the human brain accumulates different proteinaceous aggregates, such as Tau and Aβ.…”