Investigating brain clearance mechanisms involved in the removal of pathological proteins associated with neurodegenerative disease, and their potenti

Brain waste clearance has long been a popular topic of discussion within neuroscience; the brain is the most energy-consuming and waste-producing organ yet does not have a classical lymphatic system for waste removal. The closest part of the lymphatic system lies within the dural meninges, but these vessels do not enter the brain tissue, thus other mechanisms of waste clearance or transport of waste to these vessels must be at play. Disentangling waste clearance processes in the brain could provide insights into brain health, disease pathogenesis and progression, and provide novel therapeutic targets.

The glymphatic system is a paravascular waste clearance system which encompasses clearance in deep brain tissue. It has been found to clear prion-like proteins involved in neurodegenerative disease pathologies, namely beta-amyloid associated with Alzheimer's disease, tau associated with numerous dementias, and alpha synuclein associated with Parkinson's disease and Lewy body disorders. In this pathway, cerebrospinal fluid (CSF) follows penetrating arterioles (branching from pial arteries) into the brain, via the paravascular space, between the blood vessel endothelium and the astrocytic endfeet which ensheath it. The CSF moves into the interstitial space of the brain parenchyma through gaps in between the astrocytic endfeet and the water channel, aquaporin-4, which is localized at the endfeet. Inflow of fluid pushes waste-filled interstitial fluid towards the venous paravascular space, and then to the meningeal and cervical lymphatics for clearance out of the body. The glymphatic system can be upregulated and inhibited pharmacologically and has the potential to be an viable therapeutic target in neurodegenerative disease states.

Brain lymphatic endothelial cells (BLECs) are single cells in close association with meningeal blood vessels, found in the leptomeninges of zebrafish, sitting below the dura where the meningeal lymphatic vessels exist. The cells are non-lumenised, so do not form vessels, but do express lymphatic cell markers (prox1a, vgfr3, lyve1). These cells can internalize macromolecules, including beta-amyloid (1-40, and also monomeric and oligomeric forms of 1-42). Endocytosis of macromolecules is dependent on the mannose receptor 1a, which is describes as a pattern-recognition receptor, crucial for identification, binding and internalization of pathogens. This is a point of pharmacological manipulation of BLECs. These cells have also been found in mice and humans and could provide another part of the puzzle to understanding how waste is cleared from the brain, or how the brain maintains its health through surveillance.

Dysfunction of the glymphatic system or BLECs could be linked to neurodegenerative disease progression and pathological protein accumulation. Understanding these systems individually, and possible connections between them, could enhance our understanding of brain waste clearance regarding neurodegenerative diseases and other neurological conditions. In my PhD project, I intend to use zebrafish and mouse models, as well as human tissue, in collaboration with the Harrison and Rihel labs, to understand the links between these clearance mechanisms and their relationship to disease.