Verghese Joji Philip, Terry Alana, de Natale Edoardo Rosario, Politis Marios
Neurodegeneration Imaging Group, University of Exeter Medical School, London W12 0BZ, UK.
J Clin Med. 2022 Nov 25;11(23):6964. doi: 10.3390/jcm11236964.
The glymphatic system is a unique pathway that utilises end-feet Aquaporin 4 (AQP4) channels within perivascular astrocytes, which is believed to cause cerebrospinal fluid (CSF) inflow into perivascular space (PVS), providing nutrients and waste disposal of the brain parenchyma. It is theorised that the bulk flow of CSF within the PVS removes waste products, soluble proteins, and products of metabolic activity, such as amyloid-β (Aβ). In the experimental model, the glymphatic system is selectively active during slow-wave sleep, and its activity is affected by both sleep dysfunction and deprivation. Dysfunction of the glymphatic system has been proposed as a potential key driver of neurodegeneration. This hypothesis is indirectly supported by the close relationship between neurodegenerative diseases and sleep alterations, frequently occurring years before the clinical diagnosis. Therefore, a detailed characterisation of the function of the glymphatic system in human physiology and disease would shed light on its early stage pathophysiology. The study of the glymphatic system is also critical to identifying means for its pharmacological modulation, which may have the potential for disease modification. This review will critically outline the primary evidence from literature about the dysfunction of the glymphatic system in neurodegeneration and discuss the rationale and current knowledge about pharmacological modulation of the glymphatic system in the animal model and its potential clinical applications in human clinical trials.
胶质淋巴系统是一条独特的途径，它利用血管周围星形胶质细胞内的终足水通道蛋白4（AQP4）通道，据信这会导致脑脊液（CSF）流入血管周围间隙（PVS），为脑实质提供营养并处理废物。理论上，PVS内脑脊液的大量流动可清除废物、可溶性蛋白质以及代谢活动的产物，如β-淀粉样蛋白（Aβ）。在实验模型中，胶质淋巴系统在慢波睡眠期间具有选择性活性，其活性受睡眠功能障碍和睡眠剥夺的影响。胶质淋巴系统功能障碍被认为是神经退行性变的一个潜在关键驱动因素。神经退行性疾病与睡眠改变之间的密切关系间接支持了这一假说，这种睡眠改变常在临床诊断前数年就已出现。因此，详细描述胶质淋巴系统在人体生理和疾病中的功能，将有助于揭示其早期病理生理学机制。对胶质淋巴系统的研究对于确定其药理调节方法也至关重要，这可能具有疾病修饰的潜力。本综述将批判性地概述文献中关于胶质淋巴系统在神经退行性变中功能障碍的主要证据，并讨论在动物模型中对胶质淋巴系统进行药理调节的基本原理和现有知识，以及其在人体临床试验中的潜在临床应用。
