Involvement of the autophagic pathway in the progression of AMD-like retinopathy in senescence-accelerated OXYS rats

Kozhevnikova, Oyuna S.; Telegina, Darya V.; Devyatkin, V. A.; Kolosova, N. G.

doi:10.1007/s10522-018-9751-y

Cited by 34 publications

(29 citation statements)

References 36 publications

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“…3a). Our recent studies point to a modest role of apoptosis at advanced stages of retinopathy in OXYS rats [9] and preferential involvement of other types of cell death (such as autophagy and necroptosis) in the retina during AMD [14].…”

Section: Probdnf and P75 Ntr Expressionmentioning

confidence: 85%

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Immunohistochemical localization of NGF, BDNF, and their receptors in a normal and AMD-like rat retina

2019

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Background: Age-related macular degeneration (AMD) is a major cause of blindness in developed countries, and the molecular pathogenesis of AMD is poorly understood. A large body of evidence has corroborated the key role of neurotrophins in development, proliferation, differentiation, and survival of retinal cells. Neurotrophin deprivation has been proposed to contribute to retinal-cell death associated with neurodegenerative diseases. Little is known about the expression of the immature form of neurotrophins (proneurotrophins) and their mature form [e.g., nerve growth factor (proNGF and mNGF) and brain-derived neurotrophic factor (proBDNF and mBDNF)] in the retina during physiological aging and against the background of AMD. In addition, cell-specific localization of proteins NGF and BDNF in the retina during AMD development is not clear. Here, we evaluated contributions of the age-related alterations in the neurotrophin system to the development of AMD-like retinopathy in OXYS rats. Methods: Male OXYS rats at preclinical (20 days), early (3 months), and late (18 months) stages of the disease and age-matched male Wistar rats (as controls) were used. We performed immunohistochemical localization of NGF, BDNF, and their receptors TrkA, TrkB, and p75NTR by fluorescence microscopy in retinal sections from OXYS and Wistar rats. Results: We found increased NGF staining in Muller cells in 18-month-old OXYS rats (progressive stage of retinopathy). In contrast, we observed only subtle changes in the labeling of mature BDNF (mBDNF) and TrkB during the development of AMD-like retinopathy in OXYS rats. Using colocalization with vimentin and NeuN, we detected a difference in the cell type-specific localization of mBDNF between OXYS and Wistar rats. We showed that the mBDNF protein was located in Muller cells in OXYS rats, whereas in the Wistar retina, mBDNF immunoreactivity was detected in Muller cells and ganglion cells. During the development of AMD-like retinopathy, proBDNF dominated over mBDNF during increasing cell loss in the OXYS retina. Conclusions: These data indicate that alterations in the balance of neurotrophic factors in the retina are involved in the development of AMD-like retinopathy in OXYS rats and confirm their participation in the pathogenesis of AMD in humans.

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Section: Probdnf and P75 Ntr Expressionmentioning

confidence: 85%

“…This procedure was performed by a standard indirect method as described previously [10,14]. The eyes were removed and fixed in fresh 4% paraformaldehyde in PBS for 2 h, washed three times in PBS, and then cryoprotected in graded sucrose solutions (10, 20, and 30%).…”

Section: Immunofluorescent Stainingmentioning

confidence: 99%

Immunohistochemical localization of NGF, BDNF, and their receptors in a normal and AMD-like rat retina

2019

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“…Immunofluorescent staining was performed according to the standard method as described [ 5 ]. The eyes were removed and fixed in fresh 4% paraformaldehyde in PBS for 2 h, washed three times in PBS, and then cryoprotected in graded sucrose solutions (10%, 20%, and 30%).…”

Section: Methodsmentioning

confidence: 99%

“…To study age-associated disorders, we introduced a model of senescence-accelerated OXYS rats, which spontaneously develop a phenotype similar to human AMD-like retinopathy [ 5 – 10 ]. Retinopathy that develops in OXYS rats even at a young age corresponds (in terms of clinical manifestations and morphological characteristics) to the dry atrophic form of AMD in humans.…”

Section: Introductionmentioning

confidence: 99%

p62 /SQSTM1 coding plasmid prevents age related macular degeneration in a rat model

Kolosova

Kozhevnikova

Telegina

et al. 2018

Aging

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P62/SQSTM1, a multi-domain protein that regulates inflammation, apoptosis, and autophagy, has been linked to age-related pathologies. For example, previously we demonstrated that administration of p62/SQSTM1-encoding plasmid reduced chronic inflammation and alleviated osteoporosis and metabolic syndrome in animal models. Herein, we built upon these findings to investigate effect of the p62-encoding plasmid on an age-related macular degeneration (AMD), a progressive neurodegenerative ocular disease, using spontaneous retinopathy in senescence-accelerated OXYS rats as a model. Overall, the p62DNA decreased the incidence and severity of retinopathy. In retinal pigment epithelium (RPE), p62DNA administration slowed down development of the destructive alterations of RPE cells, including loss of regular hexagonal shape, hypertrophy, and multinucleation. In neuroretina, p62DNA prevented gliosis, retinal thinning, and significantly inhibited microglia/macrophages migration to the outer retina, prohibiting their subretinal accumulation. Taken together, our results suggest that the p62DNA has a strong retinoprotective effect in AMD.

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“…Age-related macular degeneration (AMD) is a leading cause of irreversible blindness in the elderly population [1] and is becoming a global crisis, with the number of affected people expected to reach 288 million by 2040 worldwide [2]. AMD is classified into two typical forms in the clinic, i.e., dry and wet, both of which can result in visual loss [3].…”

Section: Age-related Macular Degenerationmentioning

confidence: 99%

Autophagy in Age-Related Macular Degeneration: A Regulatory Mechanism of Oxidative Stress

Zhang

Bao

Cong

et al. 2020

Oxidative Medicine and Cellular Longevity

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Age-related macular degeneration (AMD) is a leading cause of severe visual loss and irreversible blindness in the elderly population worldwide. Retinal pigment epithelial (RPE) cells are the major site of pathological alterations in AMD. They are responsible for the phagocytosis of shed photoreceptor outer segments (POSs) and clearance of cellular waste under physiological conditions. Age-related, cumulative oxidative stimuli contribute to the pathogenesis of AMD. Excessive oxidative stress induces RPE cell degeneration and incomplete digestion of POSs, leading to the continuous accumulation of cellular waste (such as lipofuscin). Autophagy is a major system of degradation of damaged or unnecessary proteins. However, degenerative RPE cells in AMD patients cannot perform autophagy sufficiently to resist oxidative damage. Increasing evidence supports the idea that enhancing the autophagic process can properly alleviate oxidative injury in AMD and protect RPE and photoreceptor cells from degeneration and death, although overactivated autophagy may lead to cell death at early stages of retinal degenerative diseases. The crosstalk among the NFE2L2, PGC-1, p62, AMPK, and PI3K/Akt/mTOR pathways may play a crucial role in improving disturbed autophagy and mitigating the progression of AMD. In this review, we discuss how autophagy prevents oxidative damage in AMD, summarize potential neuroprotective strategies for therapeutic interventions, and provide an overview of these neuroprotective mechanisms.

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Involvement of the autophagic pathway in the progression of AMD-like retinopathy in senescence-accelerated OXYS rats

Cited by 34 publications

References 36 publications

Immunohistochemical localization of NGF, BDNF, and their receptors in a normal and AMD-like rat retina

Immunohistochemical localization of NGF, BDNF, and their receptors in a normal and AMD-like rat retina

p62 /SQSTM1 coding plasmid prevents age related macular degeneration in a rat model

Autophagy in Age-Related Macular Degeneration: A Regulatory Mechanism of Oxidative Stress

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