Investigating the neuroprotective effects of leptin and leptin fragment on mitochondrial morphology, function and survival signalling in neurodegenerative models

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, leptin_116-130, mirrors the neuroprotective actions of leptin. However, their effects with relation to mitochondrial function in neurodegeneration and the receptor binding of leptin_116-130 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 leptin_116-130 decrease ROS generation and promote neuron survival in oxidative stress-induced wildtype neurons, whereas only leptin_116-130 retains its neuroprotective effects in leptin receptor (ObR) knockdown neurons, suggesting that actions of leptin_116-130 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 leptin_116-130 is not restricted to the ObR activation, suggesting the potential application of leptin_116-130 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
Original language	English
Awarding Institution	University of St Andrews
Supervisor	Gayle Doherty (Supervisor)