Aquaporin-4 as the Main Element of the Glymphatic System for Clearance of Abnormal Proteins and Prevention of Neurodegeneration: A Review

Abstract

Background: In the last decade, the concept of the Glymphatic system as a complexly organized perivascular transport has been formed, it “connects” the cerebrospinal fluid with the lymphatic vessels of the meninges through the extracellular space of the brain. The exact molecular mechanisms of the functioning of the glymphatic pathway have not been fully characterized, but its key role in the cerebral clearance of metabolites and neurotoxic substances is noted. Neurodegenerative diseases affect millions of people around the world, and the most common pathologies from this heterogeneous group of diseases are Alzheimer's disease and Parkinson's disease. Their pathogenesis is based on abnormal protein aggregation, formation of neurofibrillary insoluble structures, and inefficient removal of neurotoxic metabolites. Aim: This article reviewed the evidence linking glymphatic system dysfunction and the development of human neurodegenerative diseases, and noted the key role of aquaporin-4 in the clearance of metabolites from the brain. Setting and Design: The actual sources of data were compiled and reviewed from PubMed, Scopus, and Web of Sciences from 2012 to 2023. Result and Discussion: Glial-dependent perivascular transport promotes the clearance of interstitial solutes, including beta-amyloid, synuclein, and tau protein, from the parenchymal extracellular space of the brain in normal and pathological conditions. An increase in the proportion of metabolites and pathological proteins in the dysfunction of the glymphatic pathway enhances the progression of cognitive impairment and neurodegenerative processes. In turn, the aging process, oxidative stress, and neuroinflammation in Alzheimer's disease and Parkinson's disease contribute to reactive astrogliosis and may impair glymphatic clearance. Conclusion: This review describes in detail the features of the glymphatic system and discusses that its dysfunction plays a fundamental significance in the pathological accumulation of metabolites during the progression of neurodegeneration and neuroinflammation. Understanding these processes will make it possible to take new steps in the prevention and treatment of neurodegenerative diseases.