St Andrews Research Repository

St Andrews University Home
View Item 
  •   St Andrews Research Repository
  • Biology (School of)
  • Biology
  • Biology Theses
  • View Item
  •   St Andrews Research Repository
  • Biology (School of)
  • Biology
  • Biology Theses
  • View Item
  •   St Andrews Research Repository
  • Biology (School of)
  • Biology
  • Biology Theses
  • View Item
  • Login
JavaScript is disabled for your browser. Some features of this site may not work without it.

Investigating mitochondrial dysfunction and lipid abnormalities in Alzheimer's disease

Date
03/12/2019
Author
Dey, Madhurima
Supervisor
Gunn-Moore, Frank J.
Smith, Terry K.
Funder
Alzheimer's Society. Scotland Doctoral Training Centre
RS MacDonald Charitable Trust
Keywords
Alzheimer's disease
Mitochondrial dysfunction
17β-hydroxysteroid dehydrogenase type 10
Lipid abnormalities
Human post mortem AD brain tissue
hBACE1 knock-in mouse model
Metadata
Show full item record
Altmetrics Handle Statistics
Altmetrics DOI Statistics
Abstract
Alzheimer’s disease (AD) is the most prevalent form of neurodegenerative dementia, estimated to affect 50 million people worldwide. Despite extensive research into AD, current therapeutic options provide only symptomatic relief, with no disease-modifying treatments presently available, which highlights the need to understand the aetiology of AD. Increasing evidence implicates mitochondrial dysfunction and metabolic deficits in the early stages of AD pathogenesis. In AD, the accumulation of oligomeric amyloid-β (Aβ) within the mitochondria allows it to interact with key mitochondrial proteins, such as 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) – a multifunctional protein which can modulate the cellular response to metabolic stress. Levels of 17β-HSD10 are upregulated within several disease-relevant regions of the human brain in AD, and the high affinity interaction between 17β-HSD10 and Aβ has been linked to cellular toxicity. Previous research shows that the catalytic function of 17β-HSD10 is essential to propagate the Aβ-induced toxicity, hence indicating that either inhibiting the enzyme or preventing the interaction between 17β-HSD10 and Aβ may hold potential as a point of therapeutic intervention. Therefore, the primary aim of the research presented within this project was to develop cellular models to advance screening of small molecule inhibitors of 17β-HSD10 developed by the group. HEK293 and differentiated SH-SY5Y cellular models overexpressing 17β-HSD10 showed that the toxicity arising from the protein’s interaction with Aβ may selectively impact vulnerable cells with a high metabolic demand. To explore the disease-relevant implications of metabolic deficits within the brain, lipidomics analysis was performed using a murine model of AD and human post mortem AD brain tissue, which revealed an increased susceptibility of the hippocampus to lipid dysregulation, and a potential role for lipid abnormalities in the white matter degeneration observed within the human brain in AD.
DOI
https://doi.org/10.17630/10023-18934
Type
Thesis, PhD Doctor of Philosophy
Rights
Embargo Date: 2022-10-31
Embargo Reason: Thesis restricted in accordance with University regulations. Print and electronic copy restricted until 31st October 2022
Collections
  • Biology Theses
URI
http://hdl.handle.net/10023/18934

Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.

Advanced Search

Browse

All of RepositoryCommunities & CollectionsBy Issue DateNamesTitlesSubjectsClassificationTypeFunderThis CollectionBy Issue DateNamesTitlesSubjectsClassificationTypeFunder

My Account

Login

Open Access

To find out how you can benefit from open access to research, see our library web pages and Open Access blog. For open access help contact: openaccess@st-andrews.ac.uk.

Accessibility

Read our Accessibility statement.

How to submit research papers

The full text of research papers can be submitted to the repository via Pure, the University's research information system. For help see our guide: How to deposit in Pure.

Electronic thesis deposit

Help with deposit.

Repository help

For repository help contact: Digital-Repository@st-andrews.ac.uk.

Give Feedback

Cookie policy

This site may use cookies. Please see Terms and Conditions.

Usage statistics

COUNTER-compliant statistics on downloads from the repository are available from the IRUS-UK Service. Contact us for information.

© University of St Andrews Library

University of St Andrews is a charity registered in Scotland, No SC013532.

  • Facebook
  • Twitter