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The role of plasmalogen lipids in synaptic assembly and function: Implications for neurodegenerative processes / ANNA SADILOVA

Swansea University Author: ANNA SADILOVA

  • E-Thesis – open access under embargo until: 15th July 2030

Abstract

Synaptic dysfunction is a hallmark of neurodegeneration and often precedes neuronal death. Plasmalogen lipids, abundant in the brain, have a unique conical structure that supports vesicle fusion and fission, processes essential for synaptic transmission. Declining plasmalogen levels are observed wit...

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Published: Swansea, Wales, UK 2025
Institution: Swansea University
Degree level: Master of Research
Degree name: MSc by Research
Supervisor: Angelini, Roberto ; Kenyon, Emma
URI: https://cronfa.swan.ac.uk/Record/cronfa69994
first_indexed 2025-07-17T13:33:28Z
last_indexed 2025-07-22T05:04:40Z
id cronfa69994
recordtype RisThesis
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spelling 2025-07-21T16:24:06.5105174 v2 69994 2025-07-17 The role of plasmalogen lipids in synaptic assembly and function: Implications for neurodegenerative processes 59e9d04f6387967668aec5ad1e3f7c1a ANNA SADILOVA ANNA SADILOVA true false 2025-07-17 Synaptic dysfunction is a hallmark of neurodegeneration and often precedes neuronal death. Plasmalogen lipids, abundant in the brain, have a unique conical structure that supports vesicle fusion and fission, processes essential for synaptic transmission. Declining plasmalogen levels are observed with normal aging and are further exacerbated in Alzheimer’s disease (AD), particularly in carriers of the apolipoprotein E4 (APOE4) allele, the strongest genetic risk factor for late-onset AD.However, the precise role of plasmalogens in neuronal function and neurodegeneration remains unclear. This thesis aimed to elucidate the role of plasmalogens in synaptic assembly, neuronal differentiation, and their potential involvement in reactive oxygen species (ROS)-driven neuroinflammatory processes.To explore the functional significance of plasmalogens, SH-SY5Y cells with silenced fatty acyl CoA reductase 1 (FAR1), the rate-limitng enzyme in plasmalogen biosynthesis, were differentiated into neuron-like cells and assessed for protein expression and synapse assembly. Impaired clustering of the presynaptic protein Synaptophysin 1 in FAR1 knockdown cells revealed a critical role for plasmalogens in synaptic assembly. Further analyses suggested that plasmalogen depletion alters vesicle size, influences ROS degradation, and disrupts early neuronal differentiation, likely impairing cell adhesion.Additionally, this thesis introduces a cost-effective method for generating astrocytelike cells from ReNcell VM progenitors and co-culturing them with iPSC-derived neurons. This innovative approach provides a versatile platform for studying astrocytic lipid trafficking and the impact of APOE, the only lipid transport protein in the human brain and a key genetic risk factor for AD, on neuronal health.In summary, this work underscores the essential role of plasmalogen lipids in neuronal differentiation and synaptic function while establishing valuable methodologies for studying neuron-astrocyte interactions. These findings provide a foundation for future research into the molecular mechanisms of neurodegeneration, aging, and APOE-dependent lipid dysregulation, opening new avenues fortherapeutic strategies. E-Thesis Swansea, Wales, UK plasmalogen, neurodegeneration, neuron, neurolipidomics 15 7 2025 2025-07-15 ORCiD identifier: https://orcid.org/0009-0006-3109-1576 COLLEGE NANME COLLEGE CODE Swansea University Angelini, Roberto ; Kenyon, Emma Master of Research MSc by Research plasmalogen, neurodegeneration, neuron, neurolipidomics 2025-07-21T16:24:06.5105174 2025-07-17T14:28:22.3465595 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science ANNA SADILOVA 1 Under embargo Under embargo 2025-07-21T15:45:31.5517368 Output 22994850 application/pdf E-Thesis – open access true 2030-07-15T00:00:00.0000000 Copyright: The Author, Anna Sadilova, 2025. Licensed under a Creative Commons Attribution- Non-Commercial-Share Alike (CC-BY-NC-SA) license. Third party content is excluded for use under the license terms. true eng https://creativecommons.org/licenses/by-nc-sa/4.0/deed.en
title The role of plasmalogen lipids in synaptic assembly and function: Implications for neurodegenerative processes
spellingShingle The role of plasmalogen lipids in synaptic assembly and function: Implications for neurodegenerative processes
ANNA SADILOVA
title_short The role of plasmalogen lipids in synaptic assembly and function: Implications for neurodegenerative processes
title_full The role of plasmalogen lipids in synaptic assembly and function: Implications for neurodegenerative processes
title_fullStr The role of plasmalogen lipids in synaptic assembly and function: Implications for neurodegenerative processes
title_full_unstemmed The role of plasmalogen lipids in synaptic assembly and function: Implications for neurodegenerative processes
title_sort The role of plasmalogen lipids in synaptic assembly and function: Implications for neurodegenerative processes
author_id_str_mv 59e9d04f6387967668aec5ad1e3f7c1a
author_id_fullname_str_mv 59e9d04f6387967668aec5ad1e3f7c1a_***_ANNA SADILOVA
author ANNA SADILOVA
author2 ANNA SADILOVA
format E-Thesis
publishDate 2025
institution Swansea University
college_str Faculty of Medicine, Health and Life Sciences
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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
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description Synaptic dysfunction is a hallmark of neurodegeneration and often precedes neuronal death. Plasmalogen lipids, abundant in the brain, have a unique conical structure that supports vesicle fusion and fission, processes essential for synaptic transmission. Declining plasmalogen levels are observed with normal aging and are further exacerbated in Alzheimer’s disease (AD), particularly in carriers of the apolipoprotein E4 (APOE4) allele, the strongest genetic risk factor for late-onset AD.However, the precise role of plasmalogens in neuronal function and neurodegeneration remains unclear. This thesis aimed to elucidate the role of plasmalogens in synaptic assembly, neuronal differentiation, and their potential involvement in reactive oxygen species (ROS)-driven neuroinflammatory processes.To explore the functional significance of plasmalogens, SH-SY5Y cells with silenced fatty acyl CoA reductase 1 (FAR1), the rate-limitng enzyme in plasmalogen biosynthesis, were differentiated into neuron-like cells and assessed for protein expression and synapse assembly. Impaired clustering of the presynaptic protein Synaptophysin 1 in FAR1 knockdown cells revealed a critical role for plasmalogens in synaptic assembly. Further analyses suggested that plasmalogen depletion alters vesicle size, influences ROS degradation, and disrupts early neuronal differentiation, likely impairing cell adhesion.Additionally, this thesis introduces a cost-effective method for generating astrocytelike cells from ReNcell VM progenitors and co-culturing them with iPSC-derived neurons. This innovative approach provides a versatile platform for studying astrocytic lipid trafficking and the impact of APOE, the only lipid transport protein in the human brain and a key genetic risk factor for AD, on neuronal health.In summary, this work underscores the essential role of plasmalogen lipids in neuronal differentiation and synaptic function while establishing valuable methodologies for studying neuron-astrocyte interactions. These findings provide a foundation for future research into the molecular mechanisms of neurodegeneration, aging, and APOE-dependent lipid dysregulation, opening new avenues fortherapeutic strategies.
published_date 2025-07-15T05:33:16Z
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