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-β 1–42 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.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia in the elderly, with increasing prevalence and no disease-modifying treatment available yet
To identify the pathways and processes associated with the differentially expressed genes (DEGs) in the hippocampus of control OXYS rats, we carried out gene annotation enrichment analysis using KEGG pathways (p < 0 05)
We found that at the stage of well-pronounced AD-like pathology in OXYS rats, genes of the calcium signaling pathway, phagosome, endocytosis, axon guidance, gap junction, and apoptosis were up- or downregulated; genes of the GnRH signaling pathway, glycerophospholipid metabolism, and neurodegenerative diseases such as AD, Huntington’s disease, and amyotrophic lateral sclerosis were upregulated; genes of the MAPK signaling cascade, insulin signaling, VEGF signal transduction, neurotrophin signaling pathway, long-term potentiation, antigen processing and presentation, T- and B-cell receptor signaling pathways, focal adhesion, ubiquitin-mediated proteolysis, lysosome, and cell cycle were downregulated (Figure 1(b))
Summary
Alzheimer’s disease (AD) is the most common form of dementia in the elderly, with increasing prevalence and no disease-modifying treatment available yet. No clinical studies conducted to date have proved a beneficial effect of antioxidant treatment in AD patients [2, 3]. Many lines of evidence suggest that mitochondrial abnormalities as well as the related oxidative stress together with synaptic degeneration are the Oxidative Medicine and Cellular Longevity earliest and most prominent features of vulnerable neurons in the brain of AD patients [5, 6]. AD-related studies have provided substantial evidence on interventions targeting mitochondria, and these data may shed some light on new strategies against AD and suggest that mitochondria-targeted antioxidants hold promise for the treatment of AD [7, 8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
