Abstract
Neuronal mitochondrial oxidative stress induced by β-amyloid (Aβ) is an early event of Alzheimer’s disease (AD). Emerging evidence has shown that antioxidant therapy represents a promising therapeutic strategy for the treatment of AD. In this study, we investigated the antioxidant activity of rhein against Aβ1-42 oligomer-induced mitochondrial oxidative stress in primary neurons and proposed a potential antioxidant pathway involved. The results suggested that rhein significantly reduced reactive oxygen species (ROS) level, reversed the depletion of mitochondrial membrane potential, and protected neurons from oxidative stress-associated apoptosis. Moreover, further study indicated that rhein activated mitochondrial biogenesis accompanied by increased cytochrome C oxidase (CytOx) and superoxide dismutase (SOD) activities. CytOx on the respiratory chain inhibited the production of ROS from electron leakage and SOD helped to eliminate excess ROS. Finally, western blot analysis confirmed that rhein remarkedly increased the protein expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) together with its upstream deacetylase sirtuin 1 (SIRT1), and activated downstream transcription factor nuclear respiratory factor 1, promoting mitochondrial biogenesis. In conclusion, our results demonstrate that rhein activates mitochondrial biogenesis regulated by the SIRT1/PGC-1α pathway as an antioxidant defense system against Aβ1-42 oligomer-induced oxidative stress. These findings broaden our knowledge of improving mitochondrial biogenesis as an approach for relieving neuronal oxidative stress in AD.
Highlights
Alzheimer’s disease (AD), the most common neurodegenerative disease, is characterized by memory loss and cognitive dysfunction (Alzheimer’s Association, 2021)
After 48 h, the curve grew slowly and gradually reached the plateau phase. These results demonstrated that the prepared Aβ1-42 depicted the typical aggregation kinetic process of monomeroligomer-protofibril-fibril
Considering that oxidative stress can be effectively alleviated through mitochondrial biogenesis, we focused on the effects of rhein on enzymes related to mitochondrial biogenesis, such as cytochrome C oxidase (CytOx) in the mitochondrial respiratory complex IV and antioxidant enzyme superoxide dismutase (SOD)
Summary
Alzheimer’s disease (AD), the most common neurodegenerative disease, is characterized by memory loss and cognitive dysfunction (Alzheimer’s Association, 2021). Mounting evidence indicates neuronal oxidative stress induced by β-amyloid (Aβ) is considered to be a critical pathological event in AD, the etiology of AD has not been fully elucidated (Lin and Beal, 2006; Borger et al, 2011; Swerdlow, 2018). Aβ destroys the electron respiratory chain in the mitochondrial inner membrane by reducing the activities of enzymes in mitochondrial respiratory chain complexes, especially cytochrome C oxidase (CytOx) in complex IV, leading to electron leakage and excess production of reactive oxygen species (ROS) (Atamna and Frey, 2004; Battogtokh et al, 2018; Misrani et al, 2021). Excess ROS aggravates mitochondrial dysfunction, which opens the mitochondrial permeability transition pore (mPTP), accelerates the release of cytochrome c (cyto c) into the cytosol, and subsequently induces the caspaserelated apoptosis cascade, triggering the apoptosis of neurons (Mehan et al, 2011; Xiao et al, 2019). Relieving oxidative stress is an effective therapeutic strategy for AD
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