Neuroprotective actions of leptin facilitated through balancing mitochondrial morphology and improving mitochondrial function

• Published in: Journal of neurochemistry 2020-09, Vol.155 (2), p.191-206
• Main Authors: Cheng, Ying, Buchan, Matthew, Vitanova, Karina, Aitken, Laura, Gunn‐Moore, Frank J., Ramsay, Rona R., Doherty, Gayle
• Format: Article
• Language: English
• Subjects: Aging; Alzheimer's disease; Amine oxidase (flavin-containing); Amyloid beta-Peptides - pharmacology; Animals; Antioxidants; Cell differentiation; Cell Line; Depolarization; Fusion protein; Glucose - deficiency; GTP Phosphohydrolases - antagonists & inhibitors; GTP Phosphohydrolases - biosynthesis; hippocampal; Hippocampus; Hippocampus - cytology; Hippocampus - pathology; Humans; Iodides; Ischemic Stroke - drug therapy; Leptin; Leptin - pharmacology; Mice; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - ultrastructure; Mitochondrial Dynamics - drug effects; mitochondrial fission; mitochondrial fusion; Mitochondrial Membranes - drug effects; Mitochondrial Proteins - antagonists & inhibitors; Mitochondrial Proteins - biosynthesis; mitochondrion; monoamine oxidase; Monoamine Oxidase - metabolism; Morphology; Neurodegenerative diseases; Neuroprotection; Neuroprotective Agents - pharmacology; Peptide Fragments - pharmacology; Perfusion; Proteins; Reactive Oxygen Species - metabolism; Tau protein
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.15003

Mitochondrial dysfunction has a recognised role in the progression of Alzheimer's disease (AD) pathophysiology. Cerebral perfusion becomes increasingly inefficient throughout ageing, leading to unbalanced mitochondrial dynamics. This effect is exaggerated by amyloid β (Aβ) and phosphorylated tau, two hallmark proteins of AD pathology. A neuroprotective role for the adipose‐derived hormone, leptin, has been demonstrated in neuronal cells. However, its effects with relation to mitochondrial function in AD remain largely unknown. To address this question, we have used both a glucose–serum‐deprived (CGSD) model of ischaemic stroke in SH‐SY5Y cells and a Aβ1–42‐treatment model of AD in differentiated hippocampal cells. Using a combination of 5,5’,6,6’‐tetrachloro‐1,1’,3,3’‐tetraethylbenzimidazolylcarbocyanine iodide (JC‐1) and MitoRed staining techniques, we show that leptin prevents depolarisation of the mitochondrial membrane and excessive mitochondrial fragmentation induced by both CGSD and Aβ1–42. Thereafter, we used ELISAs and a number of activity assays to reveal the biochemical underpinnings of these processes. Specifically, leptin was seen to inhibit up‐regulation of the mitochondrial fission protein Fis1 and down‐regulation of the mitochondrial fusion protein, Mfn2. Furthermore, leptin was seen to up‐regulate the expression and activity of the antioxidant enzyme, monoamine oxidase B. Herein we provide the first demonstration that leptin is sufficient to protect against aberrant mitochondrial dynamics and resulting loss of function induced by both CGSD and Aβ1–42. We conclude that the established neuroprotective actions of leptin may be facilitated through regulation of mitochondrial dynamics. The amelioration of mitochondrial dysfunction in neurodegeneration such as Alzheimer’s disease, is an established strategy in the search for treatments for these disorders. In this study, we demonstrate that the anti‐obesity hormone, leptin, can benefit mitochondrial dynamics and function through supporting mitochondrial membrane potential and balancing the expression of fission and fusion proteins, while boosting the expression and activity of mitochondrial antioxidant enzymes MAOB. Thus leptin’s neuroprotection may be facilitated through the regulation of mitochondrial function and dynamics.