Effects of leptin on mitochondrial function in models of Alzheimer's disease Ying Cheng (1st-year PhD), supervised by Dr Gayle Doherty School of Psychology and Neuroscience

1. Background 2. Hypothesis 3. Research plan Leptin may facilitate neuroprotective effects through regulating mitochondrial function in models of Alzheimer’s disease(AD). 3. Research plan Explore the role of leptin on mitochondrial morphology and function in models of AD. Explore intracellular signalling pathways through which leptin regulates mitochondrial functions and morphology. Illuminate the role of mitochondria in leptin-induced neuroprotective role in AD. Alzheimer’s disease: Alzheimer’s is one of the most common diseases that cause dementia, which leads to a loss of cognitive abilities, including reasoning, thinking, and remembering. Alzheimer’s is an irreversible, progressive brain disease that eventually destroys the ability to carry out the most basic tasks of daily living. AD has gained a large population around the world, become a leading cause of death, resulted in heavy economic burden on our society. Mitochondrial dysfunction has surfaced as one of the most discussed hypotheses associated with the etiology and underlying disease components of Alzheimer’s disease. Although their role in the cause of Alzheimer’s disease is still unclear, it is wide accepted that mitochondrial dysfunction, abnormal mitochondrial dynamics and degradation by mitophagy occur during the disease process, contributing to the onset and progression of Alzheimer’s disease. Mitochondrial abnormalities correlate with some of the structural changes that are seen in brains of Alzheimer’s patients. Age-related degradation of mitochondria function is a prime suspect in the pathophysiology of sporadic Alzheimer’s disease. Leptin: Epidemiological studies have revealed  that serum leptin levels are related with cognitive impairment (Holden et al., 2009) and the onset of Alzheimer’s disease (AD) (Lieb et al., 2009). Rapidly accumulating evidence from cellular and animal studies has shown that the adipose hormone leptin, a major regulator of body weight, also plays a neuroprotective role in AD(McGuire & Ishii, 2016). However, the link between leptin’s protective effect on mitochondria in AD remains largely unknown. A: Leptin-induced JAK2/STAT3 signalling pathway B: Leptin-induced PI3K/Akt signalling pathway

4.Recent Results 5. Conclusion Normal Rounded Highly interconnected 10x 72h Serum free (SF) 72h 0.1nM leptin +SF 4.Recent Results leptin increases cell viability in vitro regulates mitochondrial fission/fusion protein expression regulates mitochondrial morphology Normal Rounded Highly interconnected Poorly labelled 4.1 Leptin increases cell viability in vitro The results of LDH assay and Crystal violet assay both show that 0.1nM leptin treatment protects cells in 24h-treated groups and all concentrations of leptin play a protective role in 72h-treated groups. 4.2 Leptin regulates mitochondrial fission/fusion protein expression Compared to SF condition, 0.1nM leptin treatment regulates the expressions of Mfn2 and Fis1 (p<0.05) (D and E), but not Mfn1. In addition, leptin treatment also increases the expression of MAOA (p<0.05) (F). We observed that leptin treatment at the concentration of 0.1nM keeps ratios of Mfn1/Fis1 and Mfn2/Fis1 steadier(G and H), which suggest that leptin might be able to balance mitochondrial fission/fusion dynamics in vitro. 4.3 Leptin regulates mitochondrial morphology According to the scoring system reported by Wappler et al, mitochondria were classified as being normal, rounded, highly interconnected and poorly labelled. Category percentages were calculated for each treatment condition. Percentage of rounded mitochondria increased significantly following serum withdrawal in comparison to control. Leptin treatment conditions increased percentage of normal mitochondria in comparison to the SF condition. 5. Conclusion Leptin may facilitate neuroprotective effects through regulating mitochondrial fission & fusion dynamics in vitro.

6. Further research