MEK1/2-ERK Pathway Alterations as a Therapeutic Target in Sporadic Alzheimer's Disease: A Study in Senescence-Accelerated OXYS Rats.

Natalia A Muraleva,Nataliya G Kolosova,Natalia A Stefanova

doi:10.3390/antiox10071058

Natalia A Muraleva, Nataliya G Kolosova + Show 1 more

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https://doi.org/10.3390/antiox10071058

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Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia worldwide, with no cure. There is growing interest in mitogen-activated protein kinases (MAPKs) as possible pathogenesis-related therapeutic targets in AD. Previously, using senescence-accelerated OXYS rats, which simulate key characteristics of the sporadic AD type, we have shown that prolonged treatment with mitochondria-targeted antioxidant plastoquinonyl-decyltriphenylphosphonium (SkQ1) during active progression of AD-like pathology improves the activity of many signaling pathways (SPs) including the p38 MAPK SP. In this study, we continued to investigate the mechanisms behind anti-AD effects of SkQ1 in OXYS rats and focused on hippocampal extracellular regulated kinases’ (ERK1 and -2) activity alterations. According to high-throughput RNA sequencing results, SkQ1 eliminated differences in the expression of eight out of nine genes involved in the ERK1/2 SP, compared to untreated control (Wistar) rats. Western blotting and immunofluorescent staining revealed that SkQ1 suppressed ERK1/2 activity via reductions in the phosphorylation of kinases ERK1/2, MEK1, and MEK2. SkQ1 decreased hyperphosphorylation of tau protein, which is present in pathological aggregates in AD. Thus, SkQ1 alleviates AD pathology by suppressing MEK1/2-ERK1/2 SP activity in the OXYS rat hippocampus and may be a promising candidate drug for human AD.

Highlights

Accepted: 27 June 2021Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia worldwide, with no cure
OXYS rats, which develop neurodegenerative changes that are similar to the signs of the sporadic type (>90% of cases) of AD in humans [19], we have previously reported that treatment with SkQ1 between ages 12 and 18 months—that is, during active progression of AD-like pathology in these animals—alleviates structural neurodegenerative alterations, improves the structural and functional state of mitochondria, prevents the neuronal loss and synaptic damage, enhances a neurotrophic supply, and decreases Aβ1–42 peptide levels and tau hyperphosphorylation in the hippocampus, resulting in improvements in learning ability and memory [15,16,17]
We found that the anti-AD properties of SkQ1 are related to improvements in the activities of many intracellular processes and signaling pathway (SP) in the prefrontal cortex and hippocampus, including the p38 mitogen-activated protein kinases (MAPKs) SP [20,21], which is launched during the development of AD-like pathology in OXYS rats [22]

Summary

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia worldwide, with no cure. The prevalence of AD is increasing dramatically due to the aging of the world population. There is no effective drug for this complex disease [1], even though the investigation into the mechanisms of AD is very active. There is growing interest in mitogen-activated protein kinases (MAPKs) as potential targets for pathogenesis-directed therapy of AD. Numerous reports have revealed a relationship between the activation of MAPKs and accumulation of pathological aggregates of beta-amyloid (Aβ) and hyperphosphorylated tau protein in neurofibrillary plaques [2,3] as well as neuroinflammation [4], oxidative stress, and other hallmarks of AD. Zhu and coauthors have demonstrated that there are differences in the activation of various

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