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dc.contributor.advisorDoherty, Gayle H.
dc.contributor.authorCheng, Ying
dc.coverage.spatialxvii, 172 p.en_US
dc.description.abstractMitochondrial dysfunction has a recognized role in the pathophysiology of neurodegeneration, including ischemic stroke and Alzheimer’s disease (AD). Compelling evidence shows that leptin prevents neuronal apoptosis and enhances cognition in AD models, and a bioactive fragment, leptin₁₁₆₋₁₃₀, mirrors the neuroprotective actions of leptin. However, their effects with relation to mitochondrial function in neurodegeneration and the receptor binding of leptin₁₁₆₋₁₃₀ remain largely unknown. Based on a combined glucose-serum deprivation (CGSD) model of ischaemic stroke in human SH-SY5Y cells and an Aβ₄₂-treatment model of AD in mouse hippocampal HT-22 cells, it is shown within the thesis that leptin alleviates excessive mitochondrial fragmentation by inhibiting fission protein Fis1 and increasing fusion protein Mfn2. Leptin improves mitochondrial function through enhancing mitochondrial membrane potential and inhibiting monoamine oxidase (MAO) that is involved in the production of reactive oxygen species (ROS). Furthermore, it is found that 17β-HSD10 is a molecular target of leptin in mitochondria by showing that leptin inhibits both the expression and activity of 17β-HSD10. Leptin and the inhibition of 17β-HSD10 rebalance energy metabolism through improving neuronal glucose uptake. Notably, leptin-mediated inhibition of 17β-HSD10 is associated with better episodic memory. Both leptin and leptin116-130 decrease ROS generation and promote neuron survival in oxidative stress-induced wildtype neurons, whereas only leptin₁₁₆₋₁₃₀ retains its neuroprotective effects in leptin receptor (ObR) knockdown neurons, suggesting that actions of leptin₁₁₆₋₁₃₀ are in a ObR-independent manner. In conclusion, leptin’s established neuroprotective actions may, at least in part, be facilitated through regulating mitochondrial function and morphology. Inhibited mitochondrial 17β-HSD10 contributes to leptin’s procognitive role. The receptor binding of leptin₁₁₆₋₁₃₀ is not restricted to the ObR activation, suggesting the potential application of leptin₁₁₆₋₁₃₀ in leptin resistant individuals. These findings provide more robust evidence to support that leptin system is a potential therapeutic target in AD.en_US
dc.description.sponsorship"This work was supported by the China Scholarship Council (CSC)-St Andrews scholarship. " -- Fundingen
dc.publisherUniversity of St Andrews
dc.relationData underpinning Ying Cheng's thesis. Cheng, Y. University of St Andrews. DOI:
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 International*
dc.subjectLeptin fragmenten_US
dc.subjectMitochondrial functionen_US
dc.subjectMitochondrial morphologyen_US
dc.subjectAlzheimer's diseaseen_US
dc.subjectObR knockdownen_US
dc.subjectEpisodic memoryen_US
dc.subject.lcshMitochondrial pathologyen
dc.subject.lcshAlzheimer's diseaseen
dc.titleInvestigating the neuroprotective effects of leptin and leptin fragment on mitochondrial morphology, function and survival signalling in neurodegenerative modelsen_US
dc.contributor.sponsorChina Scholarship Council (CSC)en_US
dc.contributor.sponsorUniversity of St Andrewsen_US
dc.type.qualificationnamePhD Doctor of Philosophyen_US
dc.publisher.institutionThe University of St Andrewsen_US
dc.rights.embargoreasonThesis restricted in accordance with University regulations. Print and electronic copy restricted until 23rd March 2026en

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    Except where otherwise noted within the work, this item's licence for re-use is described as Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International