eprintid: 10192374
rev_number: 12
eprint_status: archive
userid: 699
dir: disk0/10/19/23/74
datestamp: 2024-10-04 12:26:33
lastmod: 2025-06-01 06:10:38
status_changed: 2024-10-04 12:26:33
type: thesis
metadata_visibility: show
sword_depositor: 699
creators_name: Zhang, Yumeng
title: The Role of Cholesteryl Ester in
Developmental, Ageing, and Diseased Brain
ispublished: unpub
divisions: UCL
divisions: B02
divisions: C10
divisions: D17
note: 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.
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.
date: 2024-05-28
date_type: published
oa_status: green
full_text_type: other
thesis_class: doctoral_embargoed
thesis_award: Ph.D
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 2275795
lyricists_name: Zhang, Yumeng
lyricists_id: YZHAI87
actors_name: Zhang, Yumeng
actors_name: Mustafa, Adelat
actors_id: YZHAI87
actors_id: AMUST21
actors_role: owner
actors_role: impersonator
full_text_status: public
pages: 257
institution: UCL (University College London)
department: Division of Medicine
thesis_type: Doctoral
citation:        Zhang, Yumeng;      (2024)    The Role of Cholesteryl Ester in Developmental, Ageing, and Diseased Brain.                   Doctoral thesis  (Ph.D), UCL (University College London).     Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10192374/7/Zhang_10192374_Thesis_sig_removed.pdf