p38 MAPK-dependent alphaB-crystallin phosphorylation in Alzheimer's disease-like pathology in OXYS rats.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder. Development of AD is closely related to alterations of proteostasis including the deposition of amyloid beta (Aß) and hyperphosphorylated tau in the brain. Molecular chaperones such as αB-crystallin (CryaB) can prevent aggregation of proteins and enable their correct refolding. The p38 mitogen-activated protein kinase signaling (MAPK) pathway regulates CryaB activity through phosphorylation of CryaB. Here, we examined CryaB and phospho-(p-)Ser59-CryaB protein amounts in the prefrontal cortex of the senescence-accelerated OXYS rats at different stages of the development of AD-like pathology and in Wistar rats (control). We compared this result with the changes in the expression of genes involved in the p38 MAPK signaling pathway in the prefrontal cortex of both rat strains. Manifestation and progression of AD-like pathology in OXYS rats were accompanied by an increased level of detergent-insoluble p-Ser59-CryaB in the brain cortex, while the CryaB amount did not change. p-Ser59-CryaB was absent in the detergent-soluble protein fraction of the cortex in both rat strains. Immunostaining of brain slices revealed notable colocalization of p-Ser59-CryaB with Aß in 18-month-old OXYS rats. According to RNA sequencing data, the development of AD-like pathology in OXYS rats is accompanied in the cortex by up- and downregulation of genes involved in p38 MAPK signaling. In general, we demonstrated that the manifestation AD-like pathology in OXYS rats occurs against the background of activation of p38 MAPK-dependent CryaB phosphorylation and alterations of the p38 MAPK signaling pathway. The increased p-Ser59-CryaB amount and its colocalization with Aß can be considered a response to the accumulation of protein aggregates and may be an important part of an endogenous mechanism of AD development.

[Assessment of mitochondria-associated genes for single nucleotide polymorphisms linked to the development of hypertrophic cardiomyopathy in the senescence-accelerated OXYS rats.]

Hypertrophic cardiomyopathy (HС) is a heterogeneous myocardial disease with a wide range of clinical manifestations and risk of development increasing with age along with myocardial changes characteristic of aging. The contribution of genetic component to the development of HC is obvious, however, the etiology and pathogenesis of this disease remains unclear in 50% of cases. The aim of the present study was to search for single nucleotide polymorphisms (SNPs) in mitochondria-associated genes that can contribute to the development of myocardial hypertrophy using RNA-Seq data from senescence-accelerated OXYS rats. Here we revealed SNPs with a possible negative effect on the function of the protein product in mitochondria-associated genes Fbxl4 and Slc25a32, mutations in which were not previously associated with HC. Alterations in the expression of these genes in the myocardium of OXYS rats at different stages of the development of pathological changes indicate that the revealed SNPs can contribute to the development of HC. Thus, SNPs in the Fbxl4 and Slc25a32 genes, as well as the genes themselves, can be considered promising molecular targets in the studies of the contribution of mitochondrial dysfunction to the development of myocardial hypertrophy.

VEGF and PEDF levels in the rat retina: effects of aging and AMD-like retinopathy.

Age-related macular degeneration (AMD) is the leading cause of vision loss among the elderly. By clinical signs, there are two forms of AMD: the atrophic or dry (~ 90% of all cases) and wet or neovascular AMD (~10% of cases). Anti-vascular endothelial growth factor (VEGF) intravitreal agents are the only successful treatment for wet AMD. However, there are emerging signals that anti-VEGF treatment can potentially increase development of atrophic AMD. There is neither a treatment of the dry AMD due poor understanding of the pathogenesis and retina aging process in general. We have shown previously that senescence-accelerated OXYS rats are a suitable model of dry AMD. Signs of retinopathy in OXYS rats manifest themselves by age 3 months against the background of a decline in the number of retinal pigment epithelium (RPE) cells and an alteration of choroidal microcirculation. Herein, we compared retinal expression of proteins VEGF and PEDF (pigment epithelium-derived factor) between OXYS and Wistar rats (control). The amount of the VEGF protein increased with age in the retina of both rat strains from 3 months of age. From age 3 to 24 months, this parameter was significantly lower in OXYS rats than in Wistar rats. PEDF protein concentration was significant lower in the OXYS retina only at the age of 3 months. We can conclude that development of retinopathy in OXYS rats takes place at reduced concentrations of VEGF and PEDF. Because RPE cells control the VEGF-PEDF balance, an RPE-targeted approach is a logical choice for AMD treatment and for decreasing adverse effects of anti-VEGF treatment.

[Effect of alendronate on bone tissue status of senescence-accelerated OXYS rats].

The purpose of this research was to study the effect of Alendronate on bone mineral density (BMD) and markers of bone turnover in male and female Wistar rats and senescence-accelerated OXYS rats with early development of osteoporosis. The animals were treated with Alendronate (0.84 mg/kg) during 2 months from the age of 8 months. The effect of the drug depended on genotype and sex of animals. Alendronate increased the BMD and bone formation markers osteocalcin levels in the blood of female rats OXYS with low their initial level. In Wistar rats the drug increased bone mineral density only in males, while females reduced the level of osteocalcin. The level of serum calcium did not change, but its urinary excretion in Wistar male rats and in female rats of both strains was increased. The ability to influence on the development of disease by standard treatment shows that OXYS rats are suitable models to study the pathogenesis and design of new therapeutic targets of osteoporosis.

[Development of osteoporosis in prematurely aging OXYS rats].

The early osteoporosis in OXYS rats is the presentation of accelerated senescence and earlier positioned as senile. The present study shows the changes in metabolism detected in OXYS rats in the postnatal period. They lead to the development of osteoporosis in future and may underlie the formation of reduced peak bone mass. 90 males OXYS rats used in this study aged from 10 days to 24 months and the control group consisted of 90 male Wistar rats of the matched ages. No differences in BMD in OXYS and Wistar rats at the age of 10 days and 3 months was revealed. At the age of 10 days the OXYS rats showed the higher by 40% activity of ALH--the marker of osteoblast activity--than Wistar rats; but at the age of 3 months ALH activity in OXYS was lower than in Wistar rats. The peak bone mass and BMD in Wistar rats is formed by the age of 12 months, in OXYS rats already by 6, but it did not reach the level of Wistar. The content of Ca in the blood and bone tissue changes similarly: no difference in young age, but reduces in OXYS rats after 6 months to the background of enhanced Ca excretion in urine. However, changing the mineral composition of bone in OXYS rats did not affect the mechanical strength: the absolute strength of the long bones in OXYS at 12 months was lower than that of Wistar, but at the expense of decrease by 1,7 times the cross-sectional area. We suppose that genetically determined hypoplasia of the bone tissue in OXYS rats is the starts of pathogenetic mechanisms of idiopathic osteoporosis.