Suppression of Alzheimer’s Disease-Like Pathology Progression by Mitochondria-Targeted Antioxidant SkQ1: A Transcriptome Profiling Study
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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.
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AD-related cognitive decline, behavioural test scores and senescence-associated myocardial disease may improve in murine models upon long-term or limited intake of SkQ1.
“Finally, AD-related cognitive decline, behavioural test scores and senescence-associated myocardial disease may improve in murine models upon long-term (lifelong) or limited (between 12 and 18 months of age) intake of SkQ1 [77,78,99,100,101].”
From The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence (2022) · cites this paper as [99]
CHST8 encodes carbohydrate sulfotransferase 8, which has been suggested to be enriched in Alzheimer's disease pathology progression and increased in the hippocampus of Alzheimer's disease brains.
“This enzyme has been suggested to be enriched in AD pathology progression [144] and increased in the hippocampus of AD brains [64].”
From Early onset senescence and cognitive impairment in a murine model of repeated mTBI (2021) · cites this paper as [144]
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The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence
Varesi, A., Chirumbolo, S., Campagnoli, L. I. M., Pierella, E., Piccini, G. B., Carrara, A., Ricevuti, G., Scassellati, C., Bonvicini, C., & Pascale, A. (2022) · Antioxidants · doi:10.3390/antiox11071224 · Cited by 145 · see citing works
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Self-citationEarly onset senescence and cognitive impairment in a murine model of repeated mTBI
Schwab, N., Ju, Y., & Hazrati, L.-N. (2021) · Acta Neuropathologica Communications · doi:10.1186/s40478-021-01190-x · Cited by 39 · see citing works
- Authors
- Stefanova, N. A., Ershov, N. I., & Kolosova, N. G.
- Affiliations
- Institute of Cytology and Genetics (RU)
- Novosibirsk State University (RU)
- Corresponding author
- Stefanova, Natalia A.
- Venue
- Oxidative Medicine and Cellular Longevity
- Publisher
- Wiley
- Published
- 2019-07-15
- Volume
- 2019
- Pages
- 1-17
- ISSN
- 1942-0994 (ISSN-L)
- 1942-0900
- PMC
- PMC6664545
- OpenAlex
- W2958163758
- Cited by
- 40
- References
- 56
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 5 · 2023: 5 · 2022: 8 · 2021: 6 · 2020: 7
- FWCI
- 3.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Oxidative Medicine and Cellular Longevity (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Russian Foundation for Basic Research (18-015-00320, 19-15-00044)
- Russian Science Foundation (18-015-00320, 19-15-00044)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, SkQ1, mitochondria-targeted antioxidants, OXYS rats, gene expression profiling, differentially expressed genes, hippocampus, mitochondrial function, neurotrophic factors, synaptic function, amyloid-beta, tau hyperphosphorylation, neuronal loss, glial cells, endothelial cells, apoptosis, calcium signaling, cerebrovascular system, disease-modifying therapy
- MeSH terms
- Alzheimer Disease, Animals, Antioxidants, Disease Models, Animal, Hippocampus, Male, Mitochondria, Plastoquinone, Signal Transduction, Rats, Wistar, Rats, Gene Regulatory Networks, Transcriptome
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