Early-life factors influence adult-brain vulnerability to sporadic Alzheimer’s disease (AD), but the underlying molecular mechanisms are unknown. In this study, we performed an integrated analysis of mitogen-activated protein kinases (MAPK) pathways’ (ERK1/2, JNK, and p38 MAPK) activity in the hippocampus and prefrontal cortex of OXYS rats (a model of sporadic AD) on postnatal days 3 and 10 (P3 and P10): critical periods of brain maturation. Wistar rats (healthy controls) showed extensive developmental transcriptional remodeling of all MAPK pathways. OXYS rats exhibited alterations, most pronounced in the prefrontal cortex at P3, with the JNK pathway showing the greatest divergence. At the protein level, OXYS rats failed to show the normal age-related increase in hippocampal ERK1/2 phosphorylation and in JNK1/2 levels in both regions, indicating developmental signaling deficits. p38 MAPK remained stable among Wistar and OXYS rats. Thus, delayed brain maturation, which contributes to accelerated brain aging and neurodegeneration in OXYS rats, occurs simultaneously with alterations in MAPK signaling. These aberrations potentially are able to increase brain susceptibility to age-related pathologies later in life.

This study aimed to characterize metabolomic changes in the eye lens of senescence-accelerated OXYS rats in comparison with control Wistar rats, and to identify biochemical shifts associated with genotype, age, and cataract progression. Cataract severity was clinically graded. Rats’ lenses were analyzed using quantitative 1H NMR spectroscopy at 3.6 and approximately 4.5 months of age. A total of 43 metabolites were quantified. We found that at 3.6 months of age, OXYS lenses exhibited a significant accumulation of 17 metabolites, primarily amino acids, compared to Wistar rats, suggesting an imbalance between amino acid uptake and crystallin biosynthesis. However, by 4.5 months, OXYS lenses exhibited rapid metabolic changes characterized by significant decreases in amino acid, glucose, and key energy/antioxidant markers, including NAD, adenylate energy charge, and hypotaurine. Clinical cataract grade (Grade 2 vs. 3) had a negligible impact on the overall metabolomic profile. Our results indicate that profound metabolic reorganization, including an initial amino acid excess followed by energy and antioxidant depletion, precedes the morphological manifestation of cataracts in OXYS rats. We suggest that a biochemical “point of no return” occurs early in cataractogenesis, while subsequent increase in lens opacification is a secondary consequence of preexisting metabolic disturbances.

Aging is the major risk factor for age-related macular degeneration (AMD), a leading cause of vision loss in aging populations. Increasing evidence suggests that alterations of neurotransmitter systems contribute to the pathogenesis of AMD. Although biogenic amines in the retina were first detected over 50 years ago, their age-related dynamics and role in AMD development are still poorly understood. Here, we compare age-related changes in the concentrations of norepinephrine, serotonin, dopamine, and their main metabolites in the retinas of senescence-accelerated OXYS rats that develop an AMD-like retinopathy and Wistar rats. We also assessed activities of monoamine oxidases (MAOs) and tyrosine hydroxylase and compared changes in these activities with transcriptome data on genes associated with biogenic amine pathways. The results revealed that in OXYS rats, retinal aging and progression of AMD-like retinopathy are primarily associated with alterations in the dopaminergic system. Specifically, dopamine and its main metabolite DOPAC were present in the retinas at higher levels than serotonin and 5-hydroxyindoleacetic acid. Furthermore, the development of retinopathy in OXYS rats was accompanied by elevated dopamine and DOPAC levels, decreased MAO activity, and changes in the expression of genes associated with the dopaminergic synapse signaling.

Age-related macular degeneration (AMD) is the leading cause of irreversible visual impairment worldwide. AMD development is associated with inflammation, oxidative stress, and a progressive proteostasis imbalance, in whose regulation, c-Jun N-terminal kinases (JNKs) play a crucial role. JNK inhibition is being discussed as a new way to prevent and treat AMD, but there are no data on JNK signaling in the retina and its changes with age and with AMD development. Here, for the first time, we assessed JNK-signaling activity in the retina and did not detect its age-related changes in healthy Wistar rats. By contrast, manifestation and progression of the AMD-like pathology in OXYS rats occurred simultaneously with JNK pathway activation. We also confirmed that selective JNK3 inhibitor 11H-indeno[1,2-b] quinoxalin-11-one oxime sodium salt (IQ-1S) can suppress neurodegenerative changes in the OXYS rat retina. Its effects were prevention of the destructive changes in retinal synapses and the suppression of the JNK signaling pathway activity during active progression of AMD signs in OXYS rats.

It has been proven that the preclinical period of the sporadic (>95

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder and the leading cause of senile dementia. The key risk factor for a more common (>95

Alzheimer’s disease (AD) is the most common neurodegenerative disease leading to senile dementia. It is known that the processes of neurodegeneration are closely related to neurotrophic support. In this work, using a model of AD, the OXYS strain of rapidly aging rats, CDNF deficiency in the hippocampus was first identified, and an attempt was made to compensate for it by inducing overexpression using an adeno-associated viral construct. The constructs were administered into the dorsal hippocampus of rats at the age of three months. 15 months after the administration of the construct, we showed overexpression of CDNF in the target structure but did not detect its effect on the learning and memory of animals in the Morris water maze, as well as on the accumulation of Aβ and Tau protein and the expression of genes involved in the unfolded protein response (UPR).

ObjectiveOXYS rats are a unique animal model of sporadic Alzheimer’s disease (AD) that demonstrates all the key signs of AD in humans. Studying metabolic processes in OXYS rats in comparison with control Wistar rats can contribute to understanding the mechanisms of AD development, as well as to establishing metabolomic biomarkers of AD. The main goals of the work are to establish differences in the metabolomic profiles of OXYS and Wistar rat serum at different stages of AD-like pathology (presymptomatic, early and late).MethodsNMR-based metabolomics was applied for metabolomic profiling of blood serum of OXYS and Wistar rats at the age of 20 days (presymptomatic period), 4 months (first manifestation of signs of AD) and 16 months (active development of signs).ResultsWe determined the concentrations of 55 metabolites present in rat serum. We found that age-related changes in both rat strains reflect animal maturation (20 days to 4 months) and aging (4 months to 16 months), and correspond mainly to amino acid metabolism, purine metabolism, and energy pathways. Potential AD blood biomarkers include lysine, BCAAs, alanine, ornithine, creatine, glutamine and pyruvate.ConclusionThe most significant differences between OXYS and Wistar blood metabolomes were found for 20-day-old animals, which corresponds to the preclinical period of AD development in humans. Metabolomic changes observed in the brain and blood are different and often opposite in sign. Blood serum is potentially promising fluid for AD diagnosis.

Background: Recent evidence suggests that prerequisites for Alzheimer's disease (AD) can form during prenatal and early postnatal development. These prerequisites have been identified to some extent in OXYS rats: a model of the sporadic form of AD. Objective: Here, we continue to study the role of delayed brain maturation in the development of the AD-like pathology much later in OXYS rats. Methods: We assess synaptic-density changes and gene expression profiles in the prefrontal cortex (PFC) and hippocampus of OXYS and Wistar rats (parental strain; control) between ages "postnatal day 0" (P0) and P20. Results: We found that at birth, the synaptic population in the PFC of OXYS rats is half of that in Wistar rats. The proportion of both symmetric (inhibitory) contacts and asymmetric (excitatory) contacts in the hippocampus of OXYS rats at P14 and P20 matched these parameters in Wistar rats at P7 and P14, respectively. The transcriptome analysis of the PFC and hippocampus showed that gene expression profiles related to synapses are different between Wistar and OXYS rats. Next, we identified "age-specific" genes and "brain region-specific" genes whose changes in the expression can obviously contribute to the specific features of synapse formation in OXYS rats. Finally, analyses of cell-specific (neurons, astrocytes, microglia, oligodendrocytes, and endothelial cells) gene expression suggested that at P3-P20 in the PFC and hippocampus, more than 50% of downregulated genes are associated with glia: key regulators of neural-network functioning. Conclusions: Collectively, these data indicate a delay in the formation of interneuronal connections and in their efficiency in the OXYS strain.

Age-related macular degeneration (AMD) is a complex progressive eye disease, resulting in loss of central vision in the aging population. The senescence-accelerated OXYS rats reproduce the major signs of AMD. Autophagy is a cellular degradation pathway for the breakdown of cytoplasmic components. Defects in the autophagy are linked to aging and disease pathology. The purpose of this study was to determine the daily pattern of autophagy genes expression in the retina of young and old OXYS and Wistar control rats. Retina from 3-month and 21-month-old OXYS rats and Wistar rats were collected at ZT1, ZT8 and ZT16 in Zeitgeber time units, where ZT0 represents lights on (8:00) and ZT12 represents lights off (20:00). Levels of autophagy genes expression (Atg5, Atg7, Becn1, Gabarapl1, Nbr1, Map1lc3b, p62/Sqstm1, and Ulk1) were evaluated by quantitative reverse-transcription PCR. At the age of 21 months, OXYS rats had altered diurnal expression of three key autophagy genes (Atg7, p62/Sqstm1, and Ulk1) in the retina compared to age-matched Wistar rats and 3-month-old OXYS rats. No time-of-day or age-related changes in the expression of other autophagy genes were detected in control Wistar rats. Therefore, the regulation of autophagy is impaired in OXYS rats in late stages of retinopathy. Our study highlights the importance of the autophagy pathway in the pathogenesis of AMD and suggests that dysregulation of the autophagy daily rhythms accompanies the progression of AMD-like retinopathy.

Background: It is believed that alterations in the functioning of the cytochrome P450 (CYP), which participates in metabolic transformations of endogenous polyunsaturated fatty acids (PUFAs) (with the formation of cardioprotective or cardiotoxic products), affects the development of age-related cardiovascular diseases and reduces the effectiveness of some cardioselective drugs. For example, CYP2J2 activation or CYP1B1 inhibition protects against the cardiovascular toxicity of anticancer drugs. It is currently unclear whether CYPs capable of metabolizing arachidonic acid and ω-3 PUFAs to vasodilatory and vasoconstrictive derivatives are expressed in all heart regions. Methods: The work was performed on senescence-accelerated OXYS rats featuring elevated blood pressure, OXYSb rats (an OXYS substrain with normal blood pressure), and Wistar rats as a “healthy” control. The mRNA level was determined in the right and left ventricles, the right and left atria, and the aorta of 1-, 3-, and 12-month-old rats. Results: We showed that all heart regions express CYPs capable of metabolizing arachidonic acid and ω-3 PUFAs and revealed significant differences between heart regions both in the mRNA level of genes CYP1B1, CYP2J3, and CYP1A1 and in the time course of expression changes with age. Conclusions: We noticed that expression levels of these CYPs in the heart regions and aorta differ between hypertensive OXYS rats, normotensive OXYSb rats, and healthy Wistar rats but could not detect any clear-cut patterns associated with the hypertensive status of OXYS rats.

Background: Alzheimer’s disease (AD) is the most common type of dementia in the elderly. Incomplete knowledge about the pathogenesis of this disease determines the absence of medications for the treatment of AD today. Animal models can provide the necessary knowledge to understand the mechanisms of biochemical processes occurring in the body in health and disease. Objective: To identify the most promising metabolomic predictors and biomarkers reflecting metabolic disorders in the development of AD signs. Methods: High resolution 1H NMR spectroscopy was used for quantitative metabolomic profiling of the hippocampus of OXYS rats, an animal model of sporadic AD, which demonstrates key characteristics of this disease. Animals were examined during several key periods: 20 days group corresponds to the “preclinical” period preceding the development of AD signs, during their manifestation (3 months), and active progression (18 months). Wistar rats of the same age were used as control. Results: Ranges of variation and mean concentrations were established for 59 brain metabolites. The main metabolic patterns during aging, which are involved in energy metabolism pathways and metabolic shifts of neurotransmitters, have been established. Of particular note is the significant increase of scyllo-inositol and decrease of hypotaurine in the hippocampus of OXYS rats as compared to Wistars for all studied age groups. Conclusions: We suggest that the accumulation of scyllo-inositol and the reduction of hypotaurine in the brain, even at an early age, can be considered as predictors and potential biomarkers of the development of AD signs in OXYS rats and, probably, in humans.

Visomitin eye drops are the first and, so far, the only drug based on SkQ1 – the mitochondria-targeted antioxidant 10-(6′-plastoquinonyl) decyltriphenylphosphonium, developed in the laboratories of Moscow State University under the leadership of Academician V. P. Skulachev. SkQ1 is considered as a potential tool to combat the aging program. We have previously shown that it is able to prevent and/or suppress development of all manifestations of accelerated senescence in OXYS rats, including retinopathy, similar to the age-related macular degeneration (AMD). Here, we assessed the effect of Visomitin instillations on progression of the AMD-like pathology and p38 MAPK and ERK1/2 activity in the OXYS rat retina (from the age of 9 to 12 months). Wistar and OXYS rats treated with placebo (composition identical to Visomitin with the exception of SkQ1) were used as controls. Ophthalmological examination showed that in the OXYS rats receiving placebo, retinopathy progressed and severity of clinical manifestations did not differ from the intact OXYS rats. Visomitin suppressed progression of the AMD-like pathology in the OXYS rats and significantly improved structural and functional parameters of the retinal pigment epithelium cells and state of microcirculation in the choroid, which, presumably, contributed to preservation of photoreceptors, associative and ganglion neurons. It was found that the activity of p38 MAPK and ERK1/2 in the retina of 12-month-old OXYS rats is higher than that of the Wistar rats of the same age, as indicated by the increased content of phosphorylated forms of p38 MAPK and ERK1/2 and their target protein tau (at position T181 and S396). Visomitin decreased phosphorylation of p38 MAPK, ERK1/2, and tau indicating suppression of activity of these MAPK signaling cascades. Thus, Visomitin eye drops are able to suppress progression of the AMD-like pathology in the OXYS rats and their effect is associated with the decrease in activity of the MAPK signaling cascades.

Increasing evidence on the adverse health impacts of microplastics (MPs) is available, but their associated risks to the well-being of humans and long-term impacts are poorly understood. An indicator of the remote effects of MPs may be their influence on the rate of aging. To assess the effects of MPs on the aging process, we used accelerated senescence OXYS rats that develop a complex of geriatric diseases. We prepared the polyethylene terephthalate MPs (2–6 microns in size) and in OXYS and Wistar (maternal strain) rats assessed the influence of chronic administration of MPs (10 or 100 mg/kg per day from age 1.5 to 3.5 months,) on the hematological and biochemical blood parameters, spatial learning, and memory. In addition, the effects of MPs on the development of cataracts and retinopathy, similar to age-related macular degeneration (AMD), in OXYS rats were assessed. We found that in the absence of significant changes in standard clinical blood parameters, chronic MP administration negatively affected the cognitive functions of both Wistar rats and OXYS rats. Additionally, a dose of 100 mg/kg MPs contributed to cataract and AMD progression in OXYS rats. Our results suggest that MPs may increase the rate of aging and, in the long term, lifespan.

Age-related macular degeneration (AMD) is a multifactorial neurodegenerative disease that is becoming the leading cause of irreversible vision loss in people over 55 years of age. The development of the wet form of AMD is associated with impaired permeability of the blood- retinal barrier (BRB). It was believed that the BRB does not change in the dry form of the disease, but recently it was shown that dysfunction of the BRB may also contribute to its development; however, information about the state of the BRB at different stages of AMD, especially preclinical ones, is limited. The purpose of this study was to assess the possible contribution of changes in BRB permeability to the development of signs of AMD in OXYS rats, a model of the dry form of the disease. During the period when clinical signs of AMD in OXYS rats are absent (age 20 days), during their manifestation (~5 months) and progression (at 12 and 18 months), the permeability of the BRB for Evans blue dye and the retinal contents of the tight junction proteins occludin, claudin-5, and zonula occludens-1 (ZO-1) were assessed. Wistar rats of the same age served as controls. In OXYS rats, a decrease in the permeability of the BRB was detected, which may result in a violation of the trophic supply of the retina, as well as an increase in the level of occludin during the progression of signs of AMD. ZO-1 level decreased with age, but no interstrain differences were detected. Analysis of retinal transcriptomes (RNA-seq data) showed that in rats of both strains changes in the expression of genes included (according to KEGG) in the category of tight junctions are maximum in the period from 20 days to 3 months. In OXYS rats, the mRNA levels of the Dlg1, Cd1d1, Map3k5 and Arhgef2 genes at the age of 3 months and the Crb3, F11r, Cgn, Cd1d1 and Rap2c genes the age of 18 months are different compared to Wistar rats. Such changes in gene expression in the retina of OXYS rats as AMD signs develop indicate the activation of compensatory mechanisms.

Carcinogenic food-borne liver fluke infections are a serious epidemiological threat worldwide. The major complications of Opisthorchis felineus infection are chronic inflammation and biliary intraepithelial neoplasia. Although evidence has accumulated that increased reactive oxygen species production is observed in liver fluke infection, a direct relationship between the oxidative stress and biliary intraepithelial neoplasia has not been shown. Quinones and SkQ1, a derivative of plastoquinone, have been demonstrated to be cytoprotective in numerous liver injuries due to their potent antioxidant properties. This study is aimed to assess the level of biliary intraepithelial neoplasia in O. felineus-infected hamsters after treatment with mitochondria-targeted SkQ1. SkQ1 significantly reduced the biliary intraepithelial neoplasia, which was accompanied by a decrease in lipid and DNA oxidation byproducts, mRNA expression and level of proteins associated with inflammation (TNF-α, CD68) and fibrogenesis (CK7, αSMA), and was also associated with an activation of the Keap1-Nrf2 pathway. Thus, a direct relationship was found between oxidative stress and the severity of biliary intraepithelial neoplasia in O. felineus-infected hamsters. The hepatoprotective effect of plastoquinone-derivative SkQ1 was established; therefore, this compound is a promising agent in complex therapy in the treatment of opisthorchiasis.

The leading cause of vision loss in older adults is age-related macular degeneration (AMD). AMD is a multifactorial neurodegenerative disease of the retina that is becoming the leading cause of central vision loss in people over 55 years of age. The course of AMD depends on many interacting factors: genetic, environmental, and epigenetic, including changes in microRNA expression patterns. MicroRNAs are a large group of small noncoding regulatory RNA molecules that modulate the expression of target genes by blocking translation through complementary binding of messenger RNAs. The freeze–thaw stability of microRNAs in plasma/serum/urine, efficient recovery, and the availability of quantitative detection methods expand the possibilities of their use as biomarkers as well as potential mediators of physiological and pathological processes. Assessing the circulating pool of miRNAs in various biological fluids, such as blood plasma, is considered a promising approach to diagnosing AMD and assessing the effectiveness of future therapy, which may contribute to early detection of the disease and monitoring of AMD progression. The review summarizes recent studies with a focus on clinical and experimental studies of neovascular AMD, which have established the involvement of various microRNAs in the processes of pathological angiogenesis and the possibility of their use as biomarkers and therapeutic targets.

In spite of numerous studies, pathogenesis of the sporadic (not inherited) form of Alzheimer’s disease (AD) still remains largely unclear; nevertheless, there is general consensus as regards the complex involvement of neurotrophic factors and neurotransmitters in the mechanisms of this disease. In light of recent data on the physical interaction between serotonin (5-HT) receptors and receptors of the brain-derived neurotrophic factor (BDNF), the reciprocal modulation between 5-HT and BDNF systems is of particular interest, inter alia, in the context of AD development. The OXYS lineage of prematurely aging rats is a unique model of sporadic AD. Previously, it has been reported on the changed neurotrophin balance in the brain of these animals; however, the changes in the expression of BDNF and its receptors in the dynamics of development of AD symptoms has been studied insufficiently. Even less is known about the patterns of expression of 5-HT receptors in OXYS rat brain. In the present work, we have compared the expression of BDNF and its receptors, TrkB and p75 NTR , as well as serotonin 5-НТ 1А , 5-НТ 2А , 5-НТ 4 and 5-НТ 7 receptors in the brain of OXYS and Wistar rats aged 20 days, 3.5 and 18 months. The frontal cortex of 20-day-old OXYS rats demonstrated a significant increase in the mRNA level of the Bdnf , Htr2a and Htr7 genes and, at the same time, a decrease in the ratio of phosphorylated and nonphosphorylated forms of the TrkB receptor. In the hippocampus of 20-day-old OXYS rats, the mRNA levels of the Bdnf , Htr1a , Htr2a and Htr4 genes are also elevated. A substantially higher mRNA level of the above genes for 5-HT receptors was observed in the hippocampus of OXYS rats also at the age of 3.5 months, in the period of manifestation of the first AD symptoms. The nature of change in gene expression patterns indicates the potential involvement of 5-HT receptors in suppression of the TrkB receptor function in the early period of postnatal development of OXYS rats, which may be one of the mechanisms, through which 5-HT receptors are involved in the development of pathological process in the period of manifestation of AD symptoms in OXYS rats.

Numerous studies have shown that mitochondria-targeted antioxidant SkQ1 can increase the lifespan of many species and suppress the development of various age-related diseases. Previously we demonstrated that SkQ1 suppresses all manifestations of accelerated senescence in OXYS rats, including the development of the main signs of Alzheimer’s disease (AD). GABA and glutamate are two of the most abundant neurotransmitters in the central nervous system, and it was showed that changes in their signaling accompany aging and the development of AD. Previously, we showed delicate age-related changes of the components of glutamate/GABA system in Wistar and OXYS rats, a unique model of AD. Here we investigated the influence of the treatment with SkQ1 from 12 through 18 months of age (that is, during the active progression of AD-like pathology) on glutamate/GABA system in the rat hippocampus. Our data demonstrated that the neuroprotective effects of long-term administration of SkQ1 are mediated by its effect on the GABAergic but not the glutamatergic system in the hippocampus of Wistar and OXYS rats. Western blotting revealed an increase in the level of glutamate decarboxylase GAD67 in rats of both strains, a decrease in the GABA transporter GAT1 in Wistar rats, and a tendency towards abrogation of the increased level of GABA receptor subunits GABAAr1 in OXYS rats. Thus, we showed that the neuroprotective effects of long-term treatment with SkQ1 are mediated by its effect on the GABAergic but not the glutamatergic system in the hippocampus of Wistar and OXYS rats.

Aim: In this study, OXYS rats of three ages (1, 3, and 6 months), a proven model of Alzheimer's disease (AD), at various stages of disease progression were used to thoroughly study the effects of amisulpride on behavior and tau protein phosphorylation.Background: With the growing number of patients with AD, the problem of finding a cure is very acute. Neurodegeneration in AD has various causes, one of which is hyperphosphorylation of tau protein.Objective This study aimed to investigate whether amisulpride would affect pathological tau phosphorylation in AD.Methods: We assessed the influence of chronic administration of amisulpride (3 weeks, 3 mg/kg per day, intraperitoneally)-a 5-HT7 receptor inverse agonist-on behavior and tau hyperphosphorylation in OXYS rats (at ages of 1, 3, and 6 months).Results Chronic administration of amisulpride dramatically decreased tau phosphorylation in the frontal cortex and hippocampus of 3-month-old OXYS rats. Additionally, in 1- and 3-month-old rats' hippocampi, amisulpride diminished the mRNA level of the Cdk5 gene encoding one of the main tau kinases involved in the 5-HT7 receptor-induced effect on tau phosphorylation.Conclusion:Thus, We found that chronic administration of amisulpride could reduce pathological tau hyperphosphorylation while reducing anxiety. We propose amisulpride to have therapeutic potential against AD and that it can be the most effective in the early stages of the disease.