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

Kolosova, N. G.; Kozhevnikova, Oyuna S.; Telegina, Darya V.; Фурсова, А. Ж.; Stefanova, Natalia A.; Muraleva, Natalia A.; Venanzi, Franco; Sherman, Michael Y.; Kolesnikov, S. I.; Sufianov, Albert; Gabai, Vladimir L.; Shneider, Alexander

doi:10.18632/aging.101537

Cited by 24 publications

(24 citation statements)

References 31 publications

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“…This protein is widely recognized for its multiple roles in the cell and also emerged as a key factor in AD [ 30 ]. In addition, previous data demonstrated that the administration of a p62-encoding plasmid exerted a powerful anti-osteoporotic, anti-inflammatory, and retinoprotective activity in animal models [ 31 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective effects of p62(SQSTM1)-engineered lactic acid bacteria in Alzheimer’s disease: a pre-clinical study

Cecarini

Bonfili

Gogoi

et al. 2020

Aging

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Alzheimer's disease (AD) is a progressive neurodegeneration characterized by neuron death ending in memory and cognitive decline. A major concern in AD research is the identification of new therapeutics that could prevent or delay the onset of the disorder, with current treatments being effective only in reducing symptoms. In this perspective, the use of engineered probiotics as therapeutic tools for the delivery of molecules to eukaryotic cells is finding application in several disorders. This work introduces a new strategy for AD treatment based on the use of a Lactobacillus lactis strain carrying one plasmid (pExu) that contains a eukaryotic expression cassette encoding the human p62 protein. 3xTg-AD mice orally administered with these bacteria for two months showed an increased expression of endogenous p62 in the brain, with a protein delivery mechanism involving both lymphatic vessels and neural terminations, and positive effects on the major AD hallmarks. Mice showed ameliorated memory, modulation of the ubiquitin-proteasome system and autophagy, reduced levels of amyloid peptides, and diminished neuronal oxidative and inflammatory processes. Globally, we demonstrate that these extremely safe, non-pathogenic and non-invasive bacteria used as delivery vehicles for the p62 protein represent an innovative and realistic therapeutic approach in AD.

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Section: Discussionmentioning

confidence: 99%

Neuroprotective effects of p62(SQSTM1)-engineered lactic acid bacteria in Alzheimer’s disease: a pre-clinical study

Cecarini

Bonfili

Gogoi

et al. 2020

Aging

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“…Already by the age of ~3–4 months, 100% of OXYS rats develop clinical signs of retinopathy against the background of a reduction in the transverse area of the retinal pigment epithelium (RPE), impairment of choroidal microcirculation, and retinal thinning [ 8 ]. The progression of these abnormalities in OXYS rats with age is accompanied by a significant reduction in the thickness of the photoreceptor cell layer and a decrease in the number of photoreceptor cell nuclei in the outer nuclear layer (ONL), especially in the central part of the retina [ 9 , 10 ]. The significant pathological changes in the RPE manifest themselves as excessive accumulation of lipofuscin and amyloid in the RPE regions and disturbances in the morphology of the RPE sheet, including an increase in the proportion of multinucleated cells, hypertrophy, distortion of cell shape, and reactive gliosis [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Alterations of STEP46 and STEP61 Expression in the Rat Retina with Age and AMD-Like Retinopathy Development

Telegina

Kulikova

Kozhevnikova

et al. 2020

IJMS

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Tyrosine phosphatase STEP (striatal-enriched tyrosine protein phosphatase) is a brain-specific protein phosphatase and is involved in the pathogenesis of many neurodegenerative diseases. Here, we examined the impact of STEP on the development of age-related macular degeneration (AMD)-like pathology in senescence-accelerated OXYS rats. Using OXYS and Wistar rats (control), we for the first time demonstrated age-dependent changes in Ptpn5 mRNA expression, STEP46 and STEP61 protein levels, and their phosphatase activity in the retina. The increases in STEP protein levels and the decrease of total and STEP phosphatase activities in the retina (as compared with Wistar rats) preceded the manifestation of clinical signs of AMD in OXYS rats (age 20 days). There were no differences in these retinal parameters between 13-month-old Wistar rats and OXYS rats with pronounced signs of AMD. Inhibition of STEP with TC-2153 during progressive AMD-like retinopathy (from 9 to 13 months of age) reduced the thickness of the retinal inner nuclear layer, as evidenced by a decreased amount of parvalbumin-positive amacrine neurons. Prolonged treatment with TC-2153 had no effect on Ptpn5 mRNA expression, STEP46 and STEP61 protein levels, and their phosphatase activity in the OXYS retina. Thus, TC-2153 may negatively affect the retina through mechanisms unrelated to STEP.

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“…There is evidence that a suitable experimental model of AMD is senescence-accelerated OXYS rats, which spontaneously develop a phenotype similar to human age-related disorders including AMD-like retinopathy [5][6][7][8][9][10][11]. Retinopathy that develops in OXYS rats already 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%

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

Cited by 24 publications

References 31 publications

Neuroprotective effects of p62(SQSTM1)-engineered lactic acid bacteria in Alzheimer’s disease: a pre-clinical study

Neuroprotective effects of p62(SQSTM1)-engineered lactic acid bacteria in Alzheimer’s disease: a pre-clinical study

Alterations of STEP46 and STEP61 Expression in the Rat Retina with Age and AMD-Like Retinopathy Development

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

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