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

Abstract

The classic concept of the absence of lymphatic vessels in the central nervous system (CNS), suggesting the immune privilege of the brain in spite of its high metabolic rate, was predominant until recent times. On the other hand, this idea left questioned how cerebral interstitial fluid is cleared of waste products. It was generally thought that clearance depends on cerebrospinal fluid (CSF). Not long ago, an anatomically and functionally discrete paravascular 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 paravascular spaces. Once mixed with interstitial fluid and solutes in a process mediated by aquaporin-4, CSF exits through the extracellular space along venous paravascular spaces, thus being removed from the brain. This process includes the participation of perivascular glial cells due to a sieving effect of their end-feet. Such draining space resembles the peripheral lymphatic system, therefore, the term “glymphatic” (glial-lymphatic) pathway has been coined. Specific studies focused on the potential role of the glymphatic pathway in healthy and pathological conditions, including neurodegenerative diseases. This mainly concerns Alzheimer’s disease (AD), as well as hemorrhagic and ischemic neurovascular disorders; other acute degenerative processes, 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 through perivascular pathways, which enriched our insight of homeostatic processes within neural microenvironment. Under the light of these considerations, the present article aims to discuss recent findings and concepts on nervous lymphatic drainage and blood–brain barrier (BBB) in an attempt to understand how peripheral pathological conditions may be detrimental to the CNS, paving the way to neurodegeneration.

The Glymphatic System (En)during Inflammation

“…In neurodegenerative diseases, such as Alzheimer’s disease (AD), and to a lesser extent with normal aging, the glymphatic system is impaired, due at least in part to the dysregulated expression of AQP4 on the astrocytic endfeet [ 37 , 40 , 41 ]. The effect of chronic diseases on glymphatic flow has been discussed in several recent reviews [ 17 , 41 , 42 , 43 , 44 , 45 , 46 ].…”

Virus Mimetic Poly (I:C)-Primed Airway Exosomes Enter Brain and Induce Mitochondrial Reactive Oxygen Species in Microglia

“…The fact that the hippocampus selectively collects peripheral exosomes carrying inflammatory mediators suggests a new hypothesis for Alzheimer's disease development. The hippocampus and olfactory regions are anatomically close; they are connected by memory formation networks and participate in glymphatic brain clearance [44,45]. Such anatomical and functional relations likely favour exosome transmission from the nasal cavity.…”

How About Glymphatic System Function in Patients With Migraine?

“…Glymphatic system dysfunction is implicated in a variety of neurologic diseases, particularly in neurodegenerative diseases, including dementia, Parkinson's disease, and normal pressure hydrocephalus. [24] There is little evidence…”