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

Ying Cheng, Matthew Buchan, Karina Vitanova, Laura Aitken, Frank J Gunn-Moore, Rona R. Ramsay, Gayle Doherty

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)
11 Downloads (Pure)

Abstract

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 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 upregulation of the mitochondrial fission protein Fis1 and downregulation of the mitochondrial fusion protein, Mfn2. Furthermore, leptin was seen to upregulate 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.
Original languageEnglish
Article numbere15003
Pages (from-to)191-206
JournalJournal of Neurochemistry
Volume155
Issue number2
Early online date8 Apr 2020
DOIs
Publication statusPublished - 13 Oct 2020

Keywords

  • Hippocampal
  • Leptin
  • Mitochondrial fission
  • Mitochondrial fusion
  • Mitochondrion
  • Monoamine oxidase

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