Abstract
Mitochondrial dysfunction represents a hallmark of both brain aging and age-related neurodegenerative disorders including Alzheimer disease (AD). AD-related mitochondrial dysfunction is characterized by an impaired electron transport chain (ETC), subsequent decreased adenosine triphoshpate (ATP) levels, and elevated generation of reactive oxygen species (ROS). The bioactive citrus flavanone hesperetin (Hst) is known to modulate inflammatory response, to function as an antioxidant, and to provide neuroprotective properties. The efficacy in improving mitochondrial dysfunction of Hst nanocrystals (HstN) with increased bioavailability has not yet been investigated. Human SH-SY5Y cells harboring neuronal amyloid precursor protein (APP695) acted as a model for the initial phase of AD. MOCK-transfected cells served as controls. The energetic metabolite ATP was determined using a luciferase-catalyzed bioluminescence assay. The activity of mitochondrial respiration chain complexes was assessed by high-resolution respirometry using a Clarke electrode. Expression levels of mitochondrial respiratory chain complex genes were determined using quantitative real-time polymerase chain reaction (qRT-PCR). The levels of amyloid β-protein (Aβ1-40) were measured using homogeneous time-resolved fluorescence (HTRF). ROS levels, peroxidase activity, and cytochrome c activity were determined using a fluorescence assay. Compared to pure Hst dissolved in ethanol (HstP), SH-SY5Y-APP695 cells incubated with HstN resulted in significantly reduced mitochondrial dysfunction: ATP levels and respiratory chain complex activity significantly increased. Gene expression levels of RCC I, IV, and V were significantly upregulated. In comparison, the effects of HstN on SY5Y-MOCK control cells were relatively small. Pure Hst dissolved in ethanol (HstP) had almost no effect on both cell lines. Neither HstN nor HstP led to significant changes in Aβ1-40 levels. HstN and HstP were both shown to lower peroxidase activity significantly. Furthermore, HstN significantly reduced cytochrome c activity, whereas HstP had a significant effect on reducing ROS in SH-SY5Y-APP695 cells. Thus, it seems that the mechanisms involved may not be linked to altered Aβ production. Nanoflavonoids such as HstN have the potential to prevent mitochondria against dysfunction. Compared to its pure form, HstN showed a greater effect in combatting mitochondrial dysfunction. Further studies should evaluate whether HstN protects against age-related mitochondrial dysfunction and thus may contribute to late-onset AD.
Highlights
To date, more than 50 million people have developed Alzheimer disease (AD), and by the end of 2050, over 152 million will be affected [1]
We confirm that SH-SY5Y-APP695 cells are deficient with regard to adenosine triphoshpate (ATP) levels and respiration but show an increase in amyloid β-protein (Aβ) levels compared to SH-SY5Y-MOCK cells
The significant lower respiration led to reduced ATP production in SH-SY5Y-APP695 cells compared with SH-SY5Y-MOCK cells (Figure 1B)
Summary
More than 50 million people have developed Alzheimer disease (AD), and by the end of 2050, over 152 million will be affected [1]. AD is the most common form of dementia and has its origin in various disorders of the brain [2]. Antioxidants 2021, 10, 1003 research, AD is not curable yet. It is only possible to treat symptoms, which can slow, but not stop, progression of the disease. The multifactorial pathology of AD makes it difficult to develop viable therapies, and research should focus on novel targets. One promising target is mitochondrial dysfunction, which represents a final common pathway of brain aging and dementia [7]
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