Investigating the role of Glutathione Peroxidase 4 as a therapeutic target for Alzheimer’s disease using Drosophila

Greer, Peta 2024. Investigating the role of Glutathione Peroxidase 4 as a therapeutic target for Alzheimer’s disease using Drosophila. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Alzheimer’s disease (AD) is an extremely debilitating disease presenting a worldwide issue. No effective treatments have been found and there is a need to develop new and improved therapeutics. The mechanisms driving AD include the formation of amyloidbeta (A) plaques, oxidative stress, mitochondrial dysfunction and brain iron accumulation. The glutathione (GSH) system is the main cell antioxidant system and is an attractive candidate to harness in the quest for new therapies. The family of glutathione peroxidases (GPxs) are key enzymes involved in GSH executing its antioxidant effects. The GPx isoform termed glutathione peroxidase 4 (GPx4) is critical in protecting cell membranes from lipid peroxidation and a relatively new form of cell death termed ferroptosis. This thesis aimed to determine whether GPx4 could mediate protective effects against amyloid-beta-42 (A42) and to explore GPx4- regulated lipid mechanisms that might inform the AD pathomechanism. Experiments also addressed whether GPx4 could alter sleep in A42-expressing Drosophila, to attenuate sleep disturbances and thus AD-associated symptoms. I used flies with neuronal expression of A42; a 42 amino acid form of A forming the primary constituent of amyloid plaques in AD. Longevity assays showed the fly orthologue for GPx4 (PHGPx) rescues against reduced survival caused by A42 expression. Untargeted lipidomics analyses also showed PHGPx overexpression (OE) to counteract the effects of A42 on phosphatidylcholine (PC) biosynthesis pathways. Quantifying green fluorescent protein-tagged ferritin revealed potential brain iron accumulation within A42-expressing flies. Quantifying size read-outs from mitochondria in fly glutamatergic neurons showed PHGPx manipulation to reduce mitochondrial size. Night-time sleep latency read-outs revealed a sleep rescue effect caused by PHGPx knockdown. These findings support follow-up experiments to identify whether PHGPx mediates its protective effects by counteracting ferroptosis mechanisms within the A42 model. Effects of PHGPx manipulation on other behavioural parameters relevant to AD symptoms are also warranted.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Medicine
Date of First Compliant Deposit:	27 May 2025
Last Modified:	27 May 2025 08:47
URI:	https://orca.cardiff.ac.uk/id/eprint/178488

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