SkQ1 Suppresses the p38 MAPK Signaling Pathway Involved in Alzheimer's Disease-Like Pathology in OXYS Rats.

Natalia A Muraleva,Nataliya G Kolosova,Natalia A Stefanova

doi:10.3390/antiox9080676

Natalia A Muraleva, Nataliya G Kolosova + Show 1 more

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https://doi.org/10.3390/antiox9080676

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Abstract

Alzheimer’s disease (AD) is the most common type of dementia and is currently incurable, and mitogen-activated protein kinase (MAPK) p38 is implicated in the pathogenesis of AD. p38 MAPK inhibition is considered a promising strategy against AD, but there are no safe inhibitors capable of penetrating the blood–brain barrier. Earlier, we have shown that mitochondria-targeted antioxidant plastoquinonyl-decyltriphenylphosphonium (SkQ1) at nanomolar concentrations can prevent, slow down, or partially alleviate AD-like pathology in accelerated-senescence OXYS rats. Here we confirmed that dietary supplementation with SkQ1 during active progression of AD-like pathology in OXYS rats (aged 12–18 months) suppresses AD-like pathology progression, and for the first time, we showed that its effects are associated with suppression of p38 MAPK signaling pathway (MAPKsp) activity. Transcriptome analysis, western blotting, and immunofluorescent staining revealed that SkQ1 suppresses p38 MAPKsp activity in the hippocampus at the level of expression of genes involved in the p38 MAPKsp and reduces the phosphorylation of intermediate kinases (p38 MAPK and MK2) and a downstream protein (αB-crystallin). Thus, the anti-AD effects of SkQ1 are associated with improvement in the functioning of relevant signaling pathways and intracellular processes, thus making it a promising therapeutic agent for human AD.

Highlights

Alzheimer’s disease (AD) is a progressive age-related neurodegenerative disorder in the elderly and the most prevalent cause of dementia
We examined changes in mRNA expression of genes involved in the p38 MAPK signaling pathway (MAPKsp) in the hippocampus of Wistar and OXYS rats as a function of age
We have reported that treatment with SkQ1 starting from the predementia phase of AD

Summary

Introduction

Alzheimer’s disease (AD) is a progressive age-related neurodegenerative disorder in the elderly and the most prevalent cause of dementia. There are no effective treatments, and . Existing targets of AD drug research and development include amyloid beta (Aβ), Aβ metabolism/catabolism, tau protein, inflammation, cholesterol, the cholinergic system, and other neurotransmitter systems. None of them has been validated as a therapeutically effective target [1]. The hallmark of AD is defective proteostasis, namely, aggregation and accumulation of Aβ and hyperphosphorylated tau protein in neurofibrillary tangles in the brain [2,3], in combination with oxidative stress and mitochondrial dysfunction. Mitochondrial abnormalities in combination with oxidative stress are the earliest and most noticeable signs of neuronal changes in the AD brain [4]. There is strong evidence that activation of mitogen-activated protein kinase (MAPK) p38 in the human AD brain occurs in the early stage of AD [5] and plays a substantial role in the pathogenesis of AD in the brain [6]

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