Suppression of Alzheimer’s Disease-Like Pathology Progression by Mitochondria-Targeted Antioxidant SkQ1: A Transcriptome Profiling Study

Abstract

Alzheimer’s disease (AD) is the most common type of dementia, with increasing prevalence and no disease-modifying treatment available yet. There is increasing evidence—from interventions targeting mitochondria—that may shed some light on new strategies for the treatment of AD. Previously, using senescence-accelerated OXYS rats that simulate key characteristics of sporadic AD, we have shown that treatment with mitochondria-targeted antioxidant SkQ1 (plastoquinonyl-decyltriphenylphosphonium) from age 12 to 18 months (that is, during active progression of AD-like pathology)—via improvement of mitochondrial function—prevented the neuronal loss and synaptic damage, enhanced neurotrophic supply, and decreased amyloid-β1–42 protein levels and tau hyperphosphorylation in the hippocampus. In the present study, we continued to explore the mechanisms of the anti-AD effects of SkQ1 in an OXYS rat model through deep RNA sequencing (RNA-seq) and focused upon the cell-specific gene expression alterations in the hippocampus. According to RNA-seq results, OXYS rats had 1,159 differentially expressed genes (DEGs) relative to Wistar rats (control), and 6-month treatment with SkQ1 decreased their number twofold. We found that 10.5% of all DEGs in untreated (control) OXYS rats were associated with mitochondrial function, whereas SkQ1 eliminated differences in the expression of 76% of DEGs (93 from 122 genes). Using transcriptome approaches, we found that the anti-AD effects of SkQ1 are associated with an improvement of the activity of many signaling pathways and intracellular processes. SkQ1 changed the expression of genes in neuronal, glial, and endothelial cells, and these genes are related to mitochondrial function, neurotrophic and synaptic activity, calcium processes, immune and cerebrovascular systems, catabolism, degradation, and apoptosis. Thus, RNA-seq analysis yields a detailed picture of transcriptional changes during the development of AD-like pathology and can point to the molecular and genetic mechanisms of action of the agents (including SkQ1) holding promise for the prevention and treatment of AD.

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

“…Earlier, we have reported that treatment with SkQ1 starting from the predementia phase of AD (consistent with the definition of progressive, amnestic mild cognitive impairment in humans) prevents the neuronal loss and synaptic damage, enhances neurotrophic supply, and decreases Aβ 1-42 peptide levels and tau hyperphosphorylation in the hippocampus of OXYS rats, as well as improving the structural and functional state of mitochondria, thus improving the learning ability and memory [12][13][14][15]. In the present study, by quantifying Aβ in the hippocampus, we confirmed that dietary supplementation with SkQ1 in this age period (from 12 to 18 months) suppresses the progression of AD-like pathology in OXYS rats (Table 1).…”

“…The therapeutic effects of supplementation with SkQ1 on the AD-like pathology in OXYS rats are associated with improvement of the mitochondrial apparatus and better neurotrophic supply [11,15]. Accumulating in mitochondria of brain neurons [15], SkQ1 normalizes the expression of genes associated with mitochondria [12]. Ultimately, the reversal of structural and functional damage to mitochondria should decrease the accumulation of neurotoxic aggregates and promote the suppression of p38 MAPKsp activity.…”

“…Previously, we have shown that SkQ1 [10] at nanomolar concentrations can prevent, slow down, or partially alleviate AD-like pathology in accelerated-senescence OXYS rats [11,12]. The nontransgenic OXYS rat strain is characterized by spontaneously developing key signs of AD in humans [13].…”

“…The sequence of their development in OXYS rats is consistent with the modern understanding of the pathogenesis of the most common, i.e., sporadic (>90% of cases) form of AD: Dysfunction of mitochondria, tau protein hyperphosphorylation, an aberration of long-term post-tetanic potentiation, synaptic insufficiency, destructive changes in neurons, behavioral disorders, a decrease in cognitive functions at the early stages, aggravation of these functions during an increase in the amyloid-protein precursor level, enhanced accumulation of Aβ, and formation of Aβ plaques in the brain [12][13][14][15]. We have proved that SkQ1 can alleviate all signs of AD in OXYS rats and its effects are strongly related to the improvement of structural and functional state of mitochondria [15] as confirmed by high-throughput RNA sequencing (RNA-seq) analysis of the hippocampus of OXYS rats after dietary SkQ1 supplementation [12]. That study showed that SkQ1 affects the expression of genes associated with the structure or function of mitochondria and the key signaling pathways that are altered during the progression of AD-like pathology, especially the MAPKsp and the exclusively expressed genes related to MAPK.…”

Sirtuins, Mitochondria and the Melatonergic Pathway in Alzheimer&rsquo;s Disease<strong> </strong>

“…A large body of data also shows mitochondrial dysregulation in AD, with mitochondrial dysfunction mooted as a viable AD treatment target [6], as in many other conditions [7,8]. Targeting mitochondrial function in an AD preclinical model prevents classical AD indicants, viz tangle and plaque formation [9]. Notably, the circadian rhythm drives changes in mitochondrial function and mitochondrial rate-limiting enzymes [10], suggesting that circadian dysregulation impacts core aspects of metabolic function.…”