Abstract
Mitochondrial 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.
Date of Award | 2 Jul 2021 |
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Original language | English |
Awarding Institution |
|
Supervisor | Gayle Helane Doherty (Supervisor) |
Keywords
- Leptin
- Leptin fragment
- Mitochondrial function
- Mitochondrial morphology
- 17β-HSD10
- Neurodegeneration
- Alzheimer's disease
- ObR knockdown
- Episodic memory
Access Status
- Full text embargoed until
- 23rd March 2026