Comparative Study on Hypertension-Induced Cerebral Vascular Alterations in Two Rat Lines by Magnetic Resonance Angiography

Агафонова, И. Г.; Kotelnikov, V. N.; Kolosova, N. G.; Stonik, Valentin A.

doi:10.1007/s00723-012-0327-8

Cited by 7 publications

(3 citation statements)

References 22 publications

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“…These changes include alterations in the density and morphology of cerebral microvasculature, increased endothelial pinocytosis, decreased mitochondrial content, accumulation of collagen and perlecans in the basement membrane, loss of tight junctions and/or adherens junctions, and a blood–brain barrier breakdown with leakage of blood-borne molecules [50, 51]. According to a magnetic resonance imaging study, 12-month-old OXYS rats, when AD is progressing, undergo structural and functional alterations in cerebral blood flow typical of chronic ischemia [52, 53]. We found that OXYS rats possess altered hemorheological properties of blood resulting from abnormal red blood cell deformability and aggregation [54], which are regarded as some of the mechanisms underlying the complex etiology of AD [55], thereby impairing the oxygen transport efficiency of blood in AD.…”

Section: Resultsmentioning

confidence: 99%

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

Stefanova

Ershov

Kolosova

2019

Oxidative Medicine and Cellular Longevity

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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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Section: Resultsmentioning

confidence: 99%

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

Stefanova

Ershov

Kolosova

2019

Oxidative Medicine and Cellular Longevity

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“…Such alteration results in a mismatch between the supply and demand of oxygen and metabolic substrates during the functioning of cerebral tissue; this situation leads to neuronal dysfunction [ 16 ]. It should be noted that the signs pointing to a decrease in blood flow were also present in the hippocampus of 5-month-old OXYS rats prior to Aβ deposition, which appears at the age of approximately a year [ 17 ] against the background of chronic ischemia and of a decline of cerebrovascular reactivity [ 11 , 12 ]. A gradual decline in oxygen as well as glucose supply to the brain during aging or hypoxia manifested themselves as contributing factors to hypometabolism.…”

Section: Discussionmentioning

confidence: 99%

“…Using MRI, we showed that at the age of 12 months, when AD was progressing, OXYS rats had structural and functional alterations in the cerebral blood flow typical of chronic ischemia such as reduced cerebral blood flow and a decline of cerebrovascular reactivity in response to a vasodilatory challenge, also defined as the cerebrovascular reserve [ 11 , 12 ], as in patients with AD. In addition, we found that OXYS rats show altered hemorheological properties of blood resulting from abnormal red blood cell deformability and aggregation that are regarded as one of the mechanisms underlying the complex etiology of AD [ 13 ], impairing the oxygen transport efficiency of blood in AD.…”

Section: Introductionmentioning

confidence: 99%

Association of cerebrovascular dysfunction with the development of Alzheimer’s disease-like pathology in OXYS rats

et al. 2018

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BackgroundCerebrovascular dysfunction plays a critical role in the pathogenesis of Alzheimer’s disease (AD): the most common cause of dementia in the elderly. The involvement of neurovasculature disorders in the progression of AD is now increasingly appreciated, but whether they represent initial factors or late-stage pathological changes during the disease is unclear. Using senescence-accelerated OXYS rats, which simulate key characteristics of sporadic AD, we evaluated contributions of cerebrovascular alterations to the disease development. At preclinical, early, and advanced stages of AD-like pathology, in the hippocampus of OXYS and Wistar (control) rats, we evaluated (i) the blood vessel state by histological and electron-microscopic analyses; (ii) differences in gene expression according to RNA sequencing (RNA-Seq) to identify the metabolic processes and pathways associated with blood vessel function; (iii) the amount of vascular endothelial growth factor (VEGF) by western blot and immunohistochemical analysis.ResultsWe observed a loss of hippocampal blood vessel density and ultrastructural changes of those blood vessels in OXYS rats at the early stage of AD-like pathology. There were significant alterations in the vessels and downregulation of VEGF with an increased amount of amyloid β1–42 there at the advanced stage of the disease. According to RNA-Seq data analysis, major alterations in cerebrovascular processes of OXYS rats were associated with blood vessel development, circulatory system processes, the VEGF signaling pathway, and vascular smooth muscle contraction. At preclinical and early stages of the AD-like pathology, these processes were upregulated and then downregulated with age. At the advanced stage in OXYS rats, differentially expressed genes (DEGs) were associated with downregulation of cerebrovascular function as compared to Wistar rats. Among the 46 DEGs at the preclinical stage of the disease, 28 DEGs at the early stage, and among 85 DEGs at the advanced stage, using functional analysis and gene network construction, we identified genes (Nos1, P2rx4, Pla2g6, and Bdkrb2) probably playing a significant role in the development of cerebrovascular dysfunction in OXYS rats.ConclusionsChanges in expression of the genes functionally associated with cerebrovascular processes already in the early period of life may contribute to the development of AD-like pathology in OXYS rats.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-4480-9) contains supplementary material, which is available to authorized users.

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Vasodilatation Function of Cerebral Vessels at Arterial Hypertension in OXYS Rats

2014

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Comparative Study on Hypertension-Induced Cerebral Vascular Alterations in Two Rat Lines by Magnetic Resonance Angiography

Cited by 7 publications

References 22 publications

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

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

Association of cerebrovascular dysfunction with the development of Alzheimer’s disease-like pathology in OXYS rats

Vasodilatation Function of Cerebral Vessels at Arterial Hypertension in OXYS Rats

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