Goble, Talya; (2024) Circadian and genetic regulation of Brain Lymphatic Endothelial Cell macromolecular uptake. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The recently discovered, and evolutionarily conserved, Brain Lymphatic Endothelial Cells (BLECs, also muLECs or FGPs) reside in the meninges of zebrafish and can scavenge almost all major classes of biological macromolecules. Owing both to their location and scavenging ability, BLECs are poised to be involved in clearing solutes from the cerebrospinal fluid (CSF) and thus potentially the brain, but it is unclear what endogenous processes these cells participate in. Using the model organism that these cells were first discovered, zebrafish, this thesis probes at the endocytic capacity of BLECs and whether it is regulated by different brain states. I demonstrate that BLEC-uptake of macromolecules injected into the CSF shows variation over the day-night cycle, with uptake rates higher during the subjective day relative to the subjective night. Through a series of drug and behavioural manipulations, I identify that diurnal fluctuation in BLEC-uptake capacity is controlled by the animal’s endogenous circadian rhythm, occurring independently of both external cues, such as light, and behavioural states, such as sleep or wake. I further characterise the mannose receptor (Mrc1a) and its role in regulating diurnal fluctuations in BLEC-uptake capacity as well as BLEC development and morphology. Finally, I assess whether, like other brain clearance mechanisms, BLEC function can be altered in disease. Using zebrafish mutants for known Alzheimer’s disease risk genes, I identify that perturbation of the function of these genes early in development alters CSF flow dynamics and BLEC morphology. Together, I conclude that BLEC-uptake capacity of CSF solutes is timed to coincide with the period of greatest metabolic demand, the active day period, providing new insights into how BLECs may contribute to the complex time-dependent clearance demands of the brain.

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