An antioxidant specifically targeting mitochondria delays progression of Alzheimer’s disease-like pathology

Stefanova, Natalia A.; Muraleva, Natalia A.; Maksimova, Kseniya Yi; Rudnitskaya, Ekaterina A.; Киселева, Елена; Telegina, Darya V.; Kolosova, N. G.

doi:10.18632/aging.101054

Cited by 64 publications

(61 citation statements)

References 66 publications

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“…ROS are major contributors to loss of neuronal apoptosis. Many antioxidant compounds have been demonstrated to protect the brain from Aβ neurotoxicity [42]. Given that serious adverse effects are related to synthetic antioxidants, recent research has been focused on natural products with antioxidant properties.…”

Section: Discussionmentioning

confidence: 99%

β-Ecdysterone protects SH-SY5Y cells against β-amyloid-induced apoptosis via c-Jun N-terminal kinase- and Akt-associated complementary pathways

Niu

Zhang

et al. 2018

Laboratory Investigation

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Recently, the significantly higher incidence of Alzheimer's disease (AD) in women than in men has been attributed to the loss of neuroprotective estrogen after menopause. Does phytoestrogen have the ability to protect against amyloid-β (Aβ) toxicity? The aim of this study was to evaluate hypothesis that β-ecdysterone (β-Ecd) protects SH-SY5Y cells from Aβ-induced apoptosis by separate signaling pathways involving protein kinase B (Akt) and c-Jun N-terminal kinase (JNK). Here, we demonstrate that phytoestrogen β-Ecd inhibits Aβ-triggered mitochondrial apoptotic pathway, as indicated by Bcl-2/Bax ratio elevation, cytochrome c (cyt c) release reduction, and caspase-9 inactivation. Interestingly, β-Ecd upregulates Bcl-2 expression in SH-SY5Y cells under both basal and Aβ-challenged conditions, but downregulates Bax expression only in Aβ-challenged conditions. Subsequently, Akt-dependent NF-κB activation is required for Bcl-2 upregulation, but not Bax downregulation, in response to β-Ecd, which was validated by the use of LY294002 and Bay11-7082. Notably, β-Ecd attenuates the Aβ-evoked reactive oxygen species (ROS) production, apoptosis signal-regulating kinase 1 (ASK1) phosphorylation and JNK activation without altering the basal ASK1 phosphorylation and JNK activation. ROS-scavenging by diphenyleneiodonium (DPI) abrogated the ability of β-Ecd to alter the activation of ASK1. Simultaneously, inhibition of JNK by SP600125 abolished β-Ecd-induced Bax downregulation in Aβ-challenged SH-SY5Y cells, whereas LY294002 failed to do so. Consequently, β-Ecd possesses neuroprotection by different and complementary pathways, which together promote a Bcl-2/Bax ratio. These data support our hypothesis and suggest that β-Ecd is a promising candidate for the treatment of AD.

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Section: Discussionmentioning

confidence: 99%

β-Ecdysterone protects SH-SY5Y cells against β-amyloid-induced apoptosis via c-Jun N-terminal kinase- and Akt-associated complementary pathways

Niu

Zhang

et al. 2018

Laboratory Investigation

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“…Much like ubiquinone, plastiquinone acts as an antioxidant by quenching superoxide. Using a rat model with an inherited over production of free radicals that present AD like pathology (OXYS model), SkQ1 supplemented via the diet was found to accumulate in neuronal mitochondria [172] . Furthermore, SkQ1 supplementation reduces A levels and tau hyperphosporylation in addition to improving memory and learning behaviours [172,173] .…”

Section: Toxin Induced Models Of Admentioning

confidence: 99%

Mitochondrial abnormalities in Parkinson's disease and Alzheimer's disease: can mitochondria be targeted therapeutically?

MacDonald

Barnes

Hastings

et al. 2018

Biochemical Society Transactions

172

106

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Mitochondrial abnormalities have been identified as a central mechanism in multiple neurodegenerative diseases and, therefore, the mitochondria have been explored as a therapeutic target. This review will focus on the evidence for mitochondrial abnormalities in the two most common neurodegenerative diseases, Parkinson's disease and Alzheimer's disease. In addition, we discuss the main strategies which have been explored in these diseases to target the mitochondria for therapeutic purposes, focusing on mitochondrially targeted antioxidants, peptides, modulators of mitochondrial dynamics and phenotypic screening outcomes.

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“…This rat model simulates key characteristics of AD including tau protein hyper-phosphorylation, synaptic losses, neuronal cell death, behavioral alterations, and a decrease in cognitive functions on the background of increase in APP levels, enhanced accumulation of Aβ, and formation of amyloid plaques in the brain.The genome of OXYS rats lacking the mutations in the App, Psen1, and Psen2 genes, which are specific for the early form of AD, also speaks in favor of the this model matching the particular criteria of sporadic AD . According to our data, the development and progression of AD-like pathology in OXYS rats may be caused by mitochondrial dysfunction -2016, Kolosova et al, 2017, Tyumentsev et al, 2018). Here we summarize our evidence supporting the validity of this assertion.…”

mentioning

confidence: 50%

“…The key role of mitochondrial dysfunction in the pathophysiology of AD is confirmed by the ability of mitochondria-targeted antioxidant SkQ1 to alleviate the neurodegenerative alterations via improvement of structural and functional state of mitochondria in OXYS rats. Namely, SkQ1 prevents the neuronal loss and synaptic damage, enhances neurotrophic supply, and decreases the amounts of toxic forms of Aβ and tau hyperphosphorylation in the hippocampus of OXYS rats, thereby resulting in improvement of cognitive function (Stefanova et al, , 2016Kolosova et al, 2017). Collectively, these data allow us to conclude that mitochondrial dysfunction appears at least to mediate or possibly even initiate pathological molecular cascades of AD-like pathology in OXYS rats.…”

mentioning

confidence: 99%

Contribution of Mitochondrial Disfunction in the Development of Sporadic Alzheimer's Disease: Evidence From Oxys Rats

Tyumentsev

Muraleva

Вавилин

et al. 2018

Book of Proceedings of the Second All-Russian Scientific Conference With International Participation "Regulation Mechanisms of

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Many lines of evidence suggest that decreased mitochondrialfunction is a hallmark of aging and that mitochondrialdysfunction has a central role in Alzheimer's disease (AD), the most common type of age-related dementia worldwide, which has no cure. The central role of mitochondria in aging was first proposed by Denham Harman, on the basis of his original theory that aging is caused by the accumulation of damage resulting from reactive oxygen species (ROS) (Harman, 2009). However, recent findings suggest that formation of ROS is neither the primary nor the initial cause of aging. Moreover, transient stress on mitochondria, including mitochondrial ROS (playing a critical role in a number of intra-and extracellular processes), elicits beneficial changes that extend the lifespan (Rose et al., 2017). Clearly, mitochondrial function regulates the rate of aging, and mitochondrial dysfunction takes the center stage in the pathophysiology of age-related neurodegenerative disorders, but the underlying mechanisms remain unclear. We explored the role of mitochondrial dysfunction in the development of sporadic late-onset AD, which accounts for ~95 % of all disease cases, using senescence-accelerated OXYS rats. This rat model simulates key characteristics of AD including tau protein hyper-phosphorylation, synaptic losses, neuronal cell death, behavioral alterations, and a decrease in cognitive functions on the background of increase in APP levels, enhanced accumulation of Aβ, and formation of amyloid plaques in the brain.The genome of OXYS rats lacking the mutations in the App, Psen1, and Psen2 genes, which are specific for the early form of AD, also speaks in favor of the this model matching the particular criteria of sporadic AD . According to our data, the development and progression of AD-like pathology in OXYS rats may be caused by mitochondrial dysfunction -2016, Kolosova et al., 2017, Tyumentsev et al., 2018). Here we summarize our evidence supporting the validity of this assertion.First, already at the age of 20 days, i.e., at the preclinical stage of the development of AD-like pathology, OXYS rats showed some characteristic changes in hippocampal mitochondria, which increased in size during the manifestation (the age of 5 months) and progression of these pathological changes (18 months). Even at this early age, OXYS rats show significantly lower respiratory complex IV activity and a tendency toward a decrease in the activity of complexes I and V. The persistent depression of respiratory chain activity in the hippocampal mitochondria of OXYS rats is observed throughout the lifespan. Simultaneously this decreased activity, OXYS rats show increased fusion, which leads to formation of larger mitochondria. Such fused highly integrated mitochondrial phenotype is thought to be geared toward upregulation of energy supply via ATP synthesis. Therefore, we did not detect any signs of energy deficiency in OXYS rats' brain up to the age of 3 months, when we estimated the brain energy metabolism by 31P NMR spectroscopy. What's more...

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An antioxidant specifically targeting mitochondria delays progression of Alzheimer’s disease-like pathology

Cited by 64 publications

References 66 publications

β-Ecdysterone protects SH-SY5Y cells against β-amyloid-induced apoptosis via c-Jun N-terminal kinase- and Akt-associated complementary pathways

β-Ecdysterone protects SH-SY5Y cells against β-amyloid-induced apoptosis via c-Jun N-terminal kinase- and Akt-associated complementary pathways

Mitochondrial abnormalities in Parkinson's disease and Alzheimer's disease: can mitochondria be targeted therapeutically?

Contribution of Mitochondrial Disfunction in the Development of Sporadic Alzheimer's Disease: Evidence From Oxys Rats

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