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Investigating Glymphatic Function In Alzheimer’s Disease Pathology

Ismail, Ozama; (2019) Investigating Glymphatic Function In Alzheimer’s Disease Pathology. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Alzheimer’s disease is fast becoming the greatest healthcare challenge of our time, with no known cure to-date. Brought about by the toxic formation of plaques of amyloid-β and tangles of tau in the brain, much is still unknown about the precise mechanisms that initiate these protein accumulations, thought to occur decades before clinical manifestation of symptoms. One theory is that an imbalance between the production of these proteins and their removal from the brain promotes retention that eventually aggregates into entities that devastate molecular and cellular machinery. Thus, targeting waste clearance mechanisms responsible for removing cerebral metabolites, including amyloid-β and tau, present novel, enthralling research targets. The glymphatic system is one such pathway that has been recently characterised. Considered a surrogate for lymphatics which are largely lacking in the brain, this fluid network relies on the water channel aquaporin-4, expressed highly on glia, thus being named “glymphatics”. In this work, first, a surgical protocol was established in the mouse brain to facilitate the delivery of tracer molecules into the cerebrospinal fluid. Direct, single time-point, histological assessment of fluorescent tracer distribution was performed to check consistency with previous characterisation of glymphatics in the mouse brain. Glymphatics were then visualised dynamically across the whole brain using magnetic resonance imaging. Glymphatic patterns were investigated in real-time by imaging fluid dynamics in the brain alongside a potent blocker of aquaporin-4. Next, imaging was used to characterise glymphatic changes and aquaporin-4 profiles in mouse models of Alzheimer’s pathology. This revealed a time-dependant relationship between glymphatics and tau accumulation. Finally, the findings were extrapolated onto humans by studying aquaporin-4 modifications in subjects with and without cognitive deficits. Here, the crucial relationship between aquaporin-4 and pathological aggregates of tau and amyloid-β was determined. Furthermore, dystrobrevin, a membrane protein linked to aquaporin-4, was also profiled in the setting of aging and amyloid-β pathology. The work presented herein elucidates the role of glymphatic perturbances in the context of Alzheimer’s disease and clarifies the implications of aquaporin-4 mediated clearance in neurodegeneration.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Investigating Glymphatic Function In Alzheimer’s Disease Pathology
Event: University College London
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms.
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/10083411
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