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E-Thesis 880 views 477 downloads

The profiling and imaging of sterol molecules in the human brain / LAUREN GRIFFITHS

Swansea University Author: LAUREN GRIFFITHS

DOI (Published version): 10.23889/SUthesis.62587

Abstract

For this project we had a unique opportunity to truly explore sterol molecules within the human brain of healthy and disease individuals. Cholesterol, and its derivative oxysterols, are quickly becoming an important topic within neurodegenerative diseases, with published literature suggesting altere...

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Published: Swansea 2023
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
Supervisor: Griffiths, William, J. ; Howell, Owain, W. ; Wang, Yuqin
URI: https://cronfa.swan.ac.uk/Record/cronfa62587
first_indexed 2023-02-06T16:21:29Z
last_indexed 2023-02-07T04:17:27Z
id cronfa62587
recordtype RisThesis
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spelling 2023-02-06T16:36:30.4548838 v2 62587 2023-02-06 The profiling and imaging of sterol molecules in the human brain ca28d466fbad3d5147dfd74fd62d8749 LAUREN GRIFFITHS LAUREN GRIFFITHS true false 2023-02-06 For this project we had a unique opportunity to truly explore sterol molecules within the human brain of healthy and disease individuals. Cholesterol, and its derivative oxysterols, are quickly becoming an important topic within neurodegenerative diseases, with published literature suggesting altered sterol profiles from the peripheral fluid in individuals with these disorders. The main aims of this work were to analyse oxysterols and cholesterol in neurodegenerative disease human brain tissue and corresponding controls using homogenisation to look whether the sterol profiles differ in Alzheimer’s disease, multiple sclerosis and cerebrotendinous xanthomatosis. We also aimed to develop and optimise a method to image cholesterol across intact brain tissue sections and quantify the cholesterol in regions of interest using mass spectrometry imaging. We successfully achieved the quantification of oxysterols in all neurological disorders named above and identified some significant differences in specific sterol pathways and metabolites in Alzheimer’s and multiple sclerosis homogenate tissue samples. Notably, we optimised a method to quantify and visualise cholesterol across intact tissue sections using isotope-labelled standards and matrix-assisted laser desorption/ ionisation (MALDI) - mass spectrometry imaging (MSI) and found significant changes in cholesterol in several regions of interest, including the lesions of human multiple sclerosis brain tissue and the inflammatory edge of white matter lesions using this method. We also observed differences in white matter brain stem regions of Huntington’s disease mouse brain tissue. These results highlight the importance of our optimised MALDI-MSI cholesterol method, identifying important changes in tissue that cannot be seen with standard immunohistochemical staining techniques. These changes could be telling of pathologies and mechanisms at play in neurodegenerative diseases and could help target biomarkers for future treatments. E-Thesis Swansea Mass spectrometry, oxysterols, cholesterol, multiple sclerosis, Alzheimer’s disease, Huntington’s disease, MALDI, liquid chromatography, mass spectrometry imaging 31 1 2023 2023-01-31 10.23889/SUthesis.62587 ORCiD identifier: https://orcid.org/0000-0002-8713-3687 COLLEGE NANME COLLEGE CODE Swansea University Griffiths, William, J. ; Howell, Owain, W. ; Wang, Yuqin Doctoral Ph.D Swansea University Research Excellence Scholarship (SURES) 2023-02-06T16:36:30.4548838 2023-02-06T16:17:27.3382438 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science LAUREN GRIFFITHS 1 62587__26489__d8e463fda8b54e45884dac93abb28cf7.pdf Griffiths_Lauren_PhD_Thesis_Final_Redacted_Signature.pdf 2023-02-06T16:33:28.6271498 Output 54646075 application/pdf E-Thesis – open access true Copyright: The author, Lauren Griffiths, 2023. true eng
title The profiling and imaging of sterol molecules in the human brain
spellingShingle The profiling and imaging of sterol molecules in the human brain
LAUREN GRIFFITHS
title_short The profiling and imaging of sterol molecules in the human brain
title_full The profiling and imaging of sterol molecules in the human brain
title_fullStr The profiling and imaging of sterol molecules in the human brain
title_full_unstemmed The profiling and imaging of sterol molecules in the human brain
title_sort The profiling and imaging of sterol molecules in the human brain
author_id_str_mv ca28d466fbad3d5147dfd74fd62d8749
author_id_fullname_str_mv ca28d466fbad3d5147dfd74fd62d8749_***_LAUREN GRIFFITHS
author LAUREN GRIFFITHS
author2 LAUREN GRIFFITHS
format E-Thesis
publishDate 2023
institution Swansea University
doi_str_mv 10.23889/SUthesis.62587
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 1
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description For this project we had a unique opportunity to truly explore sterol molecules within the human brain of healthy and disease individuals. Cholesterol, and its derivative oxysterols, are quickly becoming an important topic within neurodegenerative diseases, with published literature suggesting altered sterol profiles from the peripheral fluid in individuals with these disorders. The main aims of this work were to analyse oxysterols and cholesterol in neurodegenerative disease human brain tissue and corresponding controls using homogenisation to look whether the sterol profiles differ in Alzheimer’s disease, multiple sclerosis and cerebrotendinous xanthomatosis. We also aimed to develop and optimise a method to image cholesterol across intact brain tissue sections and quantify the cholesterol in regions of interest using mass spectrometry imaging. We successfully achieved the quantification of oxysterols in all neurological disorders named above and identified some significant differences in specific sterol pathways and metabolites in Alzheimer’s and multiple sclerosis homogenate tissue samples. Notably, we optimised a method to quantify and visualise cholesterol across intact tissue sections using isotope-labelled standards and matrix-assisted laser desorption/ ionisation (MALDI) - mass spectrometry imaging (MSI) and found significant changes in cholesterol in several regions of interest, including the lesions of human multiple sclerosis brain tissue and the inflammatory edge of white matter lesions using this method. We also observed differences in white matter brain stem regions of Huntington’s disease mouse brain tissue. These results highlight the importance of our optimised MALDI-MSI cholesterol method, identifying important changes in tissue that cannot be seen with standard immunohistochemical staining techniques. These changes could be telling of pathologies and mechanisms at play in neurodegenerative diseases and could help target biomarkers for future treatments.
published_date 2023-01-31T05:09:27Z
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score 11.453587

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