Abstract
The brain is a complex system that requires continual regulation of parenchymal pressure, osmolarity, and waste removal for optimal function; despite this, human brain lacks any obvious extension of lymphatic circulation for moderating fluid and waste regulation. We recapitulate herein a recent analysis of proteinaceous waste deposition in the human brain, its observed route of clearance, and the implications of abnormal accumulation along this clearance pathway as a potential mechanism of neurological diseases. This study uncovered an analogous staining pattern of cerebral phosphorylated tau in temporal lobe epilepsy (TLE) and chronic traumatic encephalopathy (CTE). Regardless of the underlying physiopathology, p-tau elimination occurred via circulation through the perivenous space, as predicted by a glymphatic route of clearance. Remarkably, we demonstrated that p-tau is associated with a neurological disease that can develop independent of head trauma, since in both CTE and TLE: 1) Extracellular p-tau followed unidirectional, fluid-driven pathways that led toward the space bordering large (>100 μm diameter) blood vessels; 2) Tau-positive staining occurred within astroglial cells adjacent to blood vessels, which signified transcellular transport of p-tau as a potential secondary efflux route; 3) P-tau frequently appeared clustered within the perivenous space. This waste aggregation bears significant implications in the disruption of interstitial fluid circulation, which may contribute to exacerbation of disease states. A better understanding of waste elimination in the human brain may prove significant as a therapeutic target to improve parenchymal fluid circulation, and consequently, mitigate the hydrostatic, osmotic and oncotic imbalances that often cause or exacerbate brain diseases.
Highlights
The brain milieu is made of a dense connection of neurons, glia and pericytes which coordinate with the brain’s blood vessel network to create a uniquely structured and intricate microenvironment, referred to as the “neurovascular unit”[1]
Communication of substances between the vascular and parenchymal regions is governed by the blood-brain barrier (BBB), a tight-junctioned endothelial cell layer with selective permeability[2]
There exist myriad sources of literature on the subject of waste removal from the brain parenchyma of other organisms, which have been consolidated in a recent meta-analysis[5]; the translatability of these hypothesized models from rodents to humans, remains a topic of speculation
Summary
The brain milieu is made of a dense connection of neurons, glia and pericytes which coordinate with the brain’s blood vessel network to create a uniquely structured and intricate microenvironment, referred to as the “neurovascular unit”[1]. In all cases, inhibited fluid circulation due to interstitial abnormalities (i.e., pathway blockage by waste aggregates, decreased arterial pulsatile force, etc.) is hypothesized to negatively alter the state of neurological conditions such as epilepsy and Alzheimer’s disease, inasmuch as the presence of extracellular waste may lead to an osmotic influx of water molecules from cerebral blood flow to the parenchymal space. This shift in osmolarity contributes to an elevated intracranial pressure (ICP) and in epilepsy, such activity could lead to ictal transition and blood-brain barrier disruption (BBBD)[10,11].
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