Zhang, Yumeng;
(2024)
The Role of Cholesteryl Ester in
Developmental, Ageing, and Diseased Brain.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Cholesterol homeostasis plays a critical role in the function of neural cell membranes and several metabolic pathways in the brain. Abnormal cholesterol accumulation in cells can impede their functionalities. To prevent the toxic build-up of cholesterol, excess brain cholesterol can be enzymatically converted into cholesteryl esters by acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1) and stored as intracellular lipid droplets. Myelin, supplied by oligodendrocytes in the brain, houses the majority (70-80%) of the brain cholesterol, which is primarily synthesised de novo. In recent years, abnormalities in brain cholesterol homeostasis have been reported to be linked to several age-related neurodegenerative diseases, and ACAT1 has been proposed as a therapeutic target for Alzheimer’s disease (AD). My project aims to reveal the role of oligodendrocyte cholesterol esters in age-related neurodegenerative diseases. Experiments documented in this thesis using immunohistochemistry methods to characterise ACAT1 expression in both oligodendrocyte precursor cells and oligodendrocytes in mice. I have also investigated the effects of ACAT1 deficiency in the brains of ageing and acute demyelination mouse models. I attempted to directly reveal the distribution of cholesteryl ester in the myelin sheath through a classic cholesterol staining method, Filipin staining, and other indirect methods. Additionally, lipidomic analysis was performed to reveal age-related trends in the level of cholesterol and neutral lipids, including cholesteryl esters, diacylglycerol and triacylglycerol, in brain white matter. The effect of lacking cholesteryl ester on oligodendrocyte precursor cells and oligodendrocytes was then investigated through histological analysis of the brains of mice with conditional knockout of ACAT1 in oligodendrocyte lineage cells. Functional analysis of ACAT1 deficiency in the AD mouse model was examined by behavioural test and then complemented by immunohistochemistry methods. In conclusion, this thesis employs various experimental methods to elucidate the significant role of cholesterol esters in developing, ageing and diseased mouse brains.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The Role of Cholesteryl Ester in Developmental, Ageing, and Diseased Brain |
| Language: | English |
| Additional information: | Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL 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/10192374 |
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