Prevention of Age-Related Macular Degeneration–Like Retinopathy by Rapamycin in Rats

Kolosova, N. G.; Muraleva, Natalia A.; Zhdankina, A. A.; Stefanova, Natalia A.; Фурсова, А. Ж.; Blagosklonny, Mikhail V.

doi:10.1016/j.ajpath.2012.04.018

Cited by 71 publications

(51 citation statements)

References 56 publications

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“…The specific area of vessels with signs of partial occlusion of retinal vessels is significantly greater in young OXYS rats compared with Wistar rats. 32,33 Overall, the changes in the chorioretinal complex of OXYS rats 64,65 reflected a typical reaction to chronic hypoxia, one of the leading factors in the pathogenesis of AMD.…”

Section: Signs Of Neurodegeneration In Oxys Ratsmentioning

confidence: 99%

“…At present, we have the 102nd generation of OXYS rats with spontaneously developing cataract and accelerated senescence syndrome, which is characterized by early development of a phenotype similar to human geriatric disorders. This pathological phenotype primarily includes accelerated thymus involution, [28][29][30] retinopathy similar to human AMD, [31][32][33][34] high blood pressure, 35 and senile osteoporosis. 36-38 Accelerated brain aging manifests itself in OXYS rats as early development of behavioral and cognitive alterations against the background of neurodegenerative changes driven by an AD-like metabolic pathway.…”

Section: Introductionmentioning

confidence: 99%

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Senescence-accelerated OXYS rats: A model of age-related cognitive decline with relevance to abnormalities in Alzheimer disease

et al. 2014

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Senescence-accelerated OXYS rats are an experimental model of accelerated aging that was established from wistar stock via selection for susceptibility to cataractogenic effects of a galactose-rich diet and via subsequent inbreeding of highly susceptible rats. Currently, we have the 102nd generation of OXYS rats with spontaneously developing cataract and accelerated senescence syndrome, which means early development of a phenotype similar to human geriatric disorders, including accelerated brain aging. in recent years, our group found strong evidence that OXYS rats are a promising model for studies of the mechanisms of brain aging and neurodegenerative processes similar to those seen in Alzheimer disease (AD). The manifestation of behavioral alterations and learning and memory deficits develop since the fourth week of age, i.e., simultaneously with first signs of neurodegeneration detectable on magnetic resonance imaging and under a light microscope. in addition, impaired long-term potentiation has been demonstrated in OXYS rats by the age of 3 months. with age, neurodegenerative changes in the brain of OXYS rats become amplified. we have shown that this deterioration happens against the background of overproduction of amyloid precursor protein (AβPP), accumulation of β-amyloid (Aβ), and hyperphosphorylation of the tau protein in the hippocampus and cortex. The development of AMDlike retinopathy in OXYS rats is also accompanied by increased accumulation of Aβ in the retina. These published data suggest that the OXYS strain may serve as a spontaneous rat model of AD-like pathology and could help to decipher the pathogenesis of AD.

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Section: Signs Of Neurodegeneration In Oxys Ratsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Senescence-accelerated OXYS rats: A model of age-related cognitive decline with relevance to abnormalities in Alzheimer disease

et al. 2014

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“…Just as the dry form of human AMD, the initial alterations in the RPE cells later lead to atrophy of the choriocapillaris and the complete loss of photoreceptor cells in the OXYS rats' retinas by the age of 24 months. 12,14,15 Previously, by means of RNA sequencing (RNA-Seq), we determined that the retinopathy in OXYS rats at the first stage (age 3 months) and second stage (age 18 months) develops simultaneously with changes in mRNA levels of hundreds of genes. Most of them are linked to immune responses, inflammation, the response to oxidative stress, Ca 2C homeostasis, and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

“…[11][12][13][14][15][16] OXYS rats develop retinopathy similar to the dry form of human AMD according to the clinical signs, morphological features, and some molecular changes. In these rats, the clinical signs of retinopathy appear by the age of 3 months during a reduction in the transverse area of the RPE and impairment of choroidal microcirculation.…”

Section: Introductionmentioning

confidence: 99%

Identification of functional networks associated with cell death in the retina of OXYS rats during the development of retinopathy

et al. 2015

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Age-related macular degeneration (AMD) is a major cause of blindness in developed countries, and the molecular pathogenesis of early events in AMD is poorly understood. Senescence-accelerated OXYS rats develop AMD-like retinopathy. The aim of this study was to explore the differences in retinal gene expression between OXYS and Wistar (control) rats at age 20 d and to identify the pathways of retinal cell death involved in the OXYS retinopathy initiation and progression. Retinal mRNA profiles of 20-day-old OXYS and Wistar rats were generated at the sequencing read depth 40 mln, in triplicate, using Illumina GAIIx. A terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) assay was performed to measure the apoptosis level. GeneMANIA was used to construct interaction networks for differentially expressed (DE) apoptosis-related genes at ages 20 d and 3 and 18 months. Functional analysis was suggestive of a developmental process, signal transduction, and cell differentiation as the most enriched biological processes among 245 DE genes at age 20 d An increased level of apoptosis was observed in OXYS rats at age 20 d but not at advanced stages. We identified functional clusters in the constructed interaction networks and possible hub genes (Rasa1, cFLAR, Birc3, Cdk1, Hspa1b, Erbb3, and Ntf3). We also demonstrated the significance of the extrinsic apoptotic pathway at preclinical, early, and advanced stages of retinopathy development. Besides the cell death signaling pathways, immune system-related processes and lipid-metabolic processes showed overrepresentation in the clusters of all networks. These characteristics of the expression profile of the genes functionally associated with apoptosis may contribute to the pathogenesis of AMD-like retinopathy in senescence-accelerated OXYS rats.

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“…1,2 Furthermore, mTOR has emerged as a potential target for therapies for age-related diseases such as cardiac hypertrophy, 3 cancer, 4,5 age-related macular degeneration, 6 and neurodegenerative diseases such as Alzheimer, Parkinson, and Huntington. 7 Rapamycin suppresses accelerated, 8 physiological, 9,10 and oncogene-induced 11,12 senescence in human and rodent cells, which may explain anti-aging effects seen in mammals.…”

Section: Introductionmentioning

confidence: 99%

Chronic rapamycin treatment or lack ofS6K1does not reduce ribosome activity in vivo

et al. 2013

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reducing activity of the mtorC1/S6K1 pathway has been shown to extend lifespan in both vertebrate and invertebrate models. For instance, both pharmacological inhibition of mtorC1 with the drug rapamycin or S6K1 knockout extends lifespan in mice. Since studies with invertebrate models suggest that reducing translational activity can increase lifespan, we reasoned that the benefits of decreased mtorC1 or S6K1 activity might be due, at least in part, to a reduction of general translational activity. Here, we report that mice given a single dose of rapamycin have reduced translational activity, while mice receiving multiple injections of rapamycin over 4 weeks show no difference in translational activity compared with vehicle-injected controls. Furthermore, mice lacking S6K1 have no difference in global translational activity compared with wild-type littermates as measured by the percentage of ribosomes that are active in multiple tissues. translational activity is reduced in S6K1-knockout mice following single injection of rapamycin, demonstrating that rapamycin's effects on translation can occur independently of S6K1. taken together, these data suggest that benefits of chronic rapamycin treatment or lack of S6K1 are dissociable from potential benefits of reduced translational activity, instead pointing to a model whereby changes in translation of specific subsets of mrNas and/or translation-independent effects of reduced mtor signaling underlie the longevity benefits.

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Prevention of Age-Related Macular Degeneration–Like Retinopathy by Rapamycin in Rats

Cited by 71 publications

References 56 publications

Senescence-accelerated OXYS rats: A model of age-related cognitive decline with relevance to abnormalities in Alzheimer disease

Senescence-accelerated OXYS rats: A model of age-related cognitive decline with relevance to abnormalities in Alzheimer disease

Identification of functional networks associated with cell death in the retina of OXYS rats during the development of retinopathy

Chronic rapamycin treatment or lack ofS6K1does not reduce ribosome activity in vivo

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