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 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.
Highlights
The high energy demands of neuronal cells mean that they are reliant on mitochondrial dynamics and function (Safiulina & Kaasik, 2013)
We provide the first demonstration that leptin is sufficient to protect against aberrant mitochondrial dynamics and resulting loss of function induced by both combined glucose and serum deprivation (CGSD) and Aβ1–42
These results reveal that leptin prevents CGSD-induced changes to mitochondrial morphology by reducing Fis1 expression and increasing Mfn2 expression, which is associated with decreased fragmentation and enhanced interconnectivity of the mitochondrial network respectively
Summary
The high energy demands of neuronal cells mean that they are reliant on mitochondrial dynamics and function (Safiulina & Kaasik, 2013). Extensive evidence supports the contribution of abnormal mitochondrial function to cellular energy depletion (Divya, Amandine, & Ken, 2013; Flint, 1995), oxidative stress and neuronal loss (Lin & Beal, 2006), which are key features of neurodegenerative diseases (Burté, Carelli, Chinnery, & Yu-WaiMan, 2015; Johri & Beal, 2012; Lin & Beal, 2006) Compelling evidence from both in vivo and in vitro studies shows that amyloid-precursor protein (APP) and/or Aβ causes mitochondrial dysfunction and morphological changes (Reddy & Beal, 2008). Medium as a control, or treated with 10 μM Aβ1–42 (A9810) with or without leptin (0.1–10 nM) for 24 hr
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