AUTHOR=Natale Gianfranco , Limanaqi Fiona , Busceti Carla L. , Mastroiacovo Federica , Nicoletti Ferdinando , Puglisi-Allegra Stefano , Fornai Francesco 

TITLE=Glymphatic System as a Gateway to Connect Neurodegeneration From Periphery to CNS

JOURNAL=Frontiers in Neuroscience

VOLUME=Volume 15 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2021.639140

DOI=10.3389/fnins.2021.639140

ISSN=1662-453X

ABSTRACT=The classic concept of the absence of lymphatic vessels in the CNS, suggesting the immune privilege of the brain in spite of its high metabolic rate, was hard to die until recent times. This idea left questioned how cerebral interstitial fluid is cleared of waste products. It was generally thought that clearance depends on cerebrospinal fluid (CSF). Recently, an anatomically and functionally discrete perivascular space was revised to provide a pathway for the clearance of molecules drained within the interstitial space. According to this model, CSF enters the brain parenchyma along arterial perivascular spaces. Once mixed with interstitial fluid and solutes in a process mediated by aquaporin-4, CSF exits through the extracellular space along venous perivascular spaces, thus being removed from the brain. This includes the participation of perivascular glial cells due to a sieving effect of their endfeet. Such draining space resembles the peripheral lymphatic system, therefore, the term “glymphatic” pathway was coined. Specific studies focused on the potential role of the glymphatic pathway in health and disease, including neurodegeneration. This mainly concerns Alzheimer’s disease, as well as hemorrhagic and ischemic neurovascular disorders; acute degenerative process such as normal pressure hydrocephalus or traumatic brain injury are involved as well. Novel morphological and functional investigations also suggested alternative models to drain molecules though perivascular pathways. The present article discusses recent findings and concepts on nervous lymphatic drainage and blood-brain barrier in an attempt to understand how peripheral pathological conditions may be detrimental to the CNS, paving the way to neurodegeneration.