Age is the major risk factor in the age-related macular degeneration (AMD) which is a complex multifactor neurodegenerative disease of the retina and the main cause of irreversible vision loss in...

Mitochondrial aberrations are observed in human Alzheimer's disease (AD) and in medical conditions that increase the risk of this disorder, suggesting that mitochondrial dysfunction may contribute to pathophysiology of AD. Here, using OXYS rats that simulate key characteristics of sporadic AD, we set out to determine the role of mitochondria in the pathophysiology of this disorder. OXYS rats were treated with a mitochondria-targeted antioxidant SkQ1 from age 12 to 18 months, that is, during active progression of AD-like pathology in these animals. Dietary supplementation with SkQ1 caused this compound to accumulate in various brain regions, and it was localized mostly to neuronal mitochondria. Via improvement of structural and functional state of mitochondria, treatment with SkQ1 alleviated the structural neurodegenerative alterations, prevented the neuronal loss and synaptic damage, increased the levels of synaptic proteins, enhanced neurotrophic supply, and decreased amyloid-β1-42 protein levels and tau hyperphosphorylation in the hippocampus of OXYS rats, resulting in improvement of the learning ability and memory. Collectively, these data support that mitochondrial dysfunction may play a key role in the pathophysiology of AD and that therapies with target mitochondria are potent to normalize a wide range of cellular signaling processes and therefore slow the progression of AD.

Age-related macular degeneration (AMD) is a major cause of blindness in developed countries, and the molecular pathogenesis of early events of AMD is poorly understood. It is known that age-related alterations of retinal pigment epithelium (RPE) cells and of glial reactivity are early hallmarks of AMD. Here we evaluated contributions of the age-related alterations of the RPE and of glia to the development of AMD-like retinopathy in OXYS rats. We showed that destructive alterations in RPE cells are a primary change during the development of retinopathy in OXYS rats. Furthermore, a defect of retinal maturation and decreased immune function at the preclinical stage of retinopathy were observed in OXYS rats in addition to the impairment of RPE cell proliferation and of their capacity for division. At the active stage of the disease, the atrophic alterations increased, and reactive gliosis was observed when disease progressed, but immune function stayed weakened. Unexpectedly, we did not observe migration of microglia and macrophages into the photoreceptor layer. These results and the wide spectrum of age-related retinal alterations in humans as well as individual differences in the risk of AMD may be attributed to genetic factors and to differences in the underlying molecular events.

Alzheimer’s disease (AD) is the commonest type of late-life dementia and damages the cerebral cortex, a vulnerable brain region implicated in memory, emotion, cognition, and decision-making behavior. AD is characterized by progressive neuronal loss, but the mechanisms of cell death at different stages of the disease remain unknown. Here, by means of OXYS rats as an appropriate model of the most common (sporadic) AD form, we studied the main pathways of cell death during development of AD-like pathology, including the preclinical stage. We found that apoptosis is activated at the pre-symptomatic stage (age 20 days) correlating with the retardation of brain development in the OXYS strain early in life. Progression of the AD-like pathology was accompanied by activation of apoptosis and necroptosis resulting from a decline of autophagy-mediated proteostasis. Our results are consistent with the idea that the nature of changes in the pathways of apoptosis, autophagy, and necrosis depends on the stage of AD.

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. 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. 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. 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.

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.