Investigating mitochondrial dysfunction and lipid abnormalities in Alzheimer's disease

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.

Date of Award	3 Dec 2019
Original language	English
Awarding Institution	University of St Andrews
Supervisor	Frank J Gunn-Moore (Supervisor) & Terry K Smith (Supervisor)