Angiotensin-converting enzyme 2 (ACE2) is a key component of the renin–angiotensin system’s counter-regulatory pathway. ACE2 is a multifunctional protein whose location and form determine its catalytic and non-catalytic functions, including amino acid transport, the creation of structural complexes, adhesion, and involvement in signaling pathways. In addition, ACE2 influences neurotransmitter systems in the brain. As the main receptor for SARS-CoV-2, ACE2 has been the subject of increasing research interest. Although ACE2 levels in the brain are low, brain damage from SARS-CoV-2 increases the risk of neurodegenerative diseases. This review aims to clarify an important issue: does the temporary inactivation of ACE2 by the SARS-CoV-2 spike protein play a role in Alzheimer-like neurodegeneration, meaning that the protein may serve as a biomarker or therapeutic target?

Previously, we demonstrated the therapeutic effects of intranasal administration of human HSP70 and YB-1 proteins in various models of AD, including olfactory bulbectomized (OBX) mice. Herein, we investigated the effect of these two stress proteins on transcription in the hippocampus and cortex of OBX mice. Despite different structures, both proteins frequently caused pronounced normalizing changes in the transcription of the same genes. Thus, the genes that normalized their expression due to the action of recHSP70 or recYB-1 coincide by 61

Alzheimer’s disease (AD) is one of the most common progressive neurodegenerative diseases leading to impairments in memory, orientation, and behavior. However, significant work is still needed to fully understand the progression of such disease and develop novel therapeutic agents for AD prevention and treatment. Small extracellular vesicles (sEVs) have received attention in recent years due to their potential therapeutic effects on AD. The aim of this study was to determine the potential effect of sEVs in an in vitro model of AD. sEVs were isolated from human Wharton’s jelly mesenchymal stem cells (MSCs) by asymmetric depth filtration, a method developed recently by us. AD was modeled in vitro using cells obtained from the hippocampi of newborn 5xFAD transgenic mice carrying mutations involved in familial AD. After isolation, sEVs underwent detailed characterization that included scanning electron microscopy, nanoparticle tracking analysis, confocal microscopy, Western blotting, and Luminex assay. When added to 5xFAD hippocampal cells, sEVs were nontoxic, colocalized with neurons and astrocytes, decreased the level of Aβ peptide, and increased the synaptic density. These results support the possibility that sEVs can improve brain cell function during aging, decrease the risk of AD, and potentially be used for AD therapeutics.

After olfactory bulbectomy, animals are often used as a model of major depression or sporadic Alzheimer's disease and, hence, the status of this model is still disputable. To elucidate the nature of alterations in the expression of the genome after the operation, we analyzed transcriptomes of the cortex, hippocampus, and cerebellum of the olfactory bulbectomized (OBX) mice. Analysis of the functional significance of genes in the brain of OBX mice indicates that the balance of the GABA/glutamatergic systems is disturbed with hyperactivation of the latter in the hippocampus, leading to the development of excitotoxicity and induction of apoptosis in the background of severe mitochondrial dysfunction and astrogliosis. On top of this, the synthesis of neurotrophic factors decreases leading to the disruption of the cytoskeleton of neurons, an increase in the level of intracellular calcium, and the activation of tau protein hyperphosphorylation. Moreover, the acetylcholinergic system is deficient in the background of the hyperactivation of acetylcholinesterase. Importantly, the activity of the dopaminergic, endorphin, and opiate systems in OBX mice decreases, leading to hormonal dysfunction. On the other hand, genes responsible for the regulation of circadian rhythms, cell migration, and innate immunity are activated in OBX animals. All this takes place in the background of a drastic downregulation of ribosomal protein genes in the brain. The obtained results indicate that OBX mice represent a model of Alzheimer's disease with elements of major depression.

Alzheimer’s disease (AD) is a severe neurodegenerative disease that affects millions of people around the world. The increasing prevalence of AD correlates with increasing life expectancy and aging populations in developed countries. Since AD is a multifactorial disease and includes various pathological processes, such as: synaptic dysfunction, neuroinflammation, oxidative stress, protein misfolding, etc., an integrated approach aimed simultaneously at several targets may be effective and slow down the progression of the disease. Cell therapy and its further development in the form of transplantation of cellular vesicles and especially mitochondria are a very promising approach for the treatment of neurodegeneration. The use of synaptosomes, due to the uniqueness of their content, may become a new stage in the development of complex therapy for neurodegenerative diseases and AD in particular. This review discusses the preparation and composition of synaptosomes, as well as the possibilities and advantages of their use as transporters for the delivery of synaptic mitochondria and other biologically active substances to the brain.

Alzheimer’s disease (AD) is a severe neurodegenerative condition affecting millions worldwide. Prevalence of AD correlates with increased life expectancy and aging population in the developed countries. Considering that AD is a multifactorial disease involving various pathological processes such as synaptic dysfunction, neuroinflammation, oxidative stress, and improper protein folding, a comprehensive approach targeting multiple pathways may prove effective in slowing the disease progression. Cellular therapy and its further development in the form of cell vesicle and particularly mitochondrial transplantation represent promising approaches for treating neurodegeneration. The use of synaptosomes, due to uniqueness of their contents, could mark a new stage in the development of comprehensive therapies for neurodegenerative diseases, particularly AD. Synaptosomes contain unique memory mitochondria, which differ not only in size but also in functionality compared to the mitochondria in the neuronal soma. These synaptosomal mitochondria actively participate in cellular communication and signal transmission within synapses. Synaptosomes also contain other elements such as their own protein synthesis machinery, synaptic vesicles with neurotransmitters, synaptic adhesion molecules, and microRNAs – all crucial for synaptic transmission and, consequently, cognitive processes. Complex molecular ensemble ensures maintenance of the synaptic autonomy of mitochondria. Additionally, synaptosomes, with their affinity for neurons, can serve as an optimal platform for targeted drug delivery to nerve cells. This review discusses unique composition of synaptosomes, their capabilities and advantages, as well as limitations of their suggested use as therapeutic agents for treating neurodegenerative pathologies, particularly AD.

Neurodegenerative diseases are intricate pathological conditions characterized by the progressive degeneration and death of neurons in the nervous system. As a result, researchers are increasingly focusing on strategies that use combinations of bioactive chemical compounds to convert other, more stable cell types into functional neurons. Chemical conversion has shown particular promise in astrocyte-only models; however, more realistic experimental systems include different cell types whose interactions may influence the response to chemical conversion. In this study, we investigated the effect of a multicomponent chemical cocktail on cells in mixed astro-neuronal cultures derived from the hippocampus of transgenic mice of the 5xFAD strain, a genetic model of Alzheimer’s disease (AD). In addition, we recreated a model that simulates the reduction in ACE2 receptor activity observed in COVID-19 patients due to internalization of the receptor after it binds to the coronavirus, in order to study the consequences of chemical conversion upon disruption of this enzyme activity in the brain. Our results indicate that the increase in neuronal density and the emergence of new neurons following exposure to the conversion cocktail in complex multi-component cell systems is apparent at later time points in cultures derived from non-transgenic animals as well as in cultures derived from the 5xFAD mice. This may be due to the natural increase in astroglial levels during culture degradation. Notably, ACE2 inhibition significantly affects the morphology of individual astrocytes and neurons. When we evaluated the effects of the chemical cocktail, we observed that its efficacy was influenced by both the transgenic status of the culture and the timing of the conversion cocktail administration in relation to ACE2 inhibition. Cultures derived from transgenic animals were more sensitive to both the ACE2 inhibitor and the chemical conversion agents.

Alzheimer’s disease (AD) is an incurable neurodegenerative disease that is the main cause of dementia in the elderly. When looking for new treatments for AD, attention was drawn to the multifunctional Y-box-binding protein 1 (YB-1). Previously, we revealed a positive effect of intranasal YB-1 administration on learning and spatial memory, along with a decrease in the content of cerebral β-amyloid and intensity of plaque initiation, with improved survival of cortical and hippocampal neurons in a male mouse model of AD. However, AD affects women twice as often as men, so it is of great interest to study the effects of YB-1 on aging females. Estrogens and androgens are required for the maintenance of cognitive function during aging and, apparently, may prevent the development of AD. In this work, peripheral levels of estradiol (E2) and cytokines were studied after intranasal YB-1 administration to aging female 5xFAD transgenic mice and control nontransgenic animals. In intact aging animals of both groups, a disruption of the estrous cycle and a decrease in plasma E2 levels were revealed. YB-1-treated mice exhibited no characteristic age-related decline in plasma E2 levels. YB-1 administration did not affect the peripheral level of cytokines. Thus, a novel, previously undescribed effect of YB-1 on plasma E2 levels in aging female mice is demonstrated, suggesting that YB-1 may be a promising drug in the prevention and treatment of neurodegenerative diseases. Further experiments are needed to gain a deeper insight into the mechanisms of YB-1 action.

The pandemic caused by a new strain of SARS-CоV-2 coronavirus has swept the whole world, however, despite the developed strategic directions for the treatment of coronavirus infection and intensive research in all countries, effective methods for treating this severe pathology have not yet been created. The list of drugs against COVID-19 practically does not use compounds that affect the renin-angiotensin system, in the functioning of which the ACE2 coronavirus binding receptor plays a central role. It is assumed that the virus, causing a decrease in the density of ACE2 receptors, leads to disruption of RAS activity. This review presents current research on the response of the immune system to infection with the SARS-CoV-2 virus, describes adaptive and innate cellular mechanisms, and describes a number of predictors of severe COVID-19. To write this review, a search was made in the PubMed database and the scientific electronic library eLibrary.ru. The selection of articles was carried out manually with the main goal of synthesizing data and describing the mechanisms of influence of SARS-CoV-2 on the renin-angiotensin system, and, as a result, on the activation of the adaptive and innate immune response. This review includes 53 publications, including methodological recommendations of the Ministry of Health of the Russian Federation, data from ongoing clinical trials and patents. Data from selected scientific sources were structured and visualized.

We studied the mutual influence of multipotent mesenchymal stromal cells (MMSC) isolated from human umbilical cord Wharton’s jelly and primary culture of hippocampal cell from transgenic (Tg) 5XFAD mice, a model of familial Alzheimer’s disease (AD). Antibodies to human nuclear antigen were used to identify MMSCs in “chimeric culture”; the cells belonging to neurons or astrocytes were determined by the presence of positive immunoreactivity to marker proteins MAP2 and GFAP. It was shown that the result of the interaction depends on both the cocultivation method and the age of the culture. In indirect (non-contact) cocultivation, the aggressive environment of the transgenic culture affected the survival rate and impaired the adhesive properties of the MMSCs. Pretreatment of these cells with stress proteins YB-1 and HSP70, which possess neuroprotective properties, increased the resistance of MMSCs. In young culture during contact cocultivation, the MMSCs play the role of specific strands that promote grouping of hippocampal cells of transgenic mice and formation of neurospheres. In old transgenic cultures, irrespective of the cocultivation method, the MMSCs differentiated into astrocytes, but during prolonged direct cocultivation, a part of MMSCs became immunopositive to the neuronal marker MAP2. The work shows that the interaction between the MMSCs and the hippocampal cell culture can be carried out with the participation of gap junctions as well as due to the formation of nanotubes. The results obtained indicate the presence of a complex relationship between donor MMSCs and recipient cells, which must be taken into account when introducing cell therapy into the practice of treating AD patients.

This article discusses the use of a direct ACE-2-receptor inhibitor as a model for the condi-tions that occur in the brains of Alzheimer's disease patients when infected with SARS-CoV-2. Original experimental data on the use of ACE-2-receptor blockade in primary hippocam-pal cell culture of 5xFAD mice are presented.

Idiopathic toe walking (ITW) occurs in about 5% of children. Orthopedic treatment of ITW is complicated by the lack of a known etiology. Only half of the conservative and surgical methods of treatment give a stable positive result of normalizing gait. Available data indicate that the disease is heterogeneous and multifactorial. Recently, some children with ITW have been found to have genetic variants of mutations that can lead to the development of toe walking. At the same time, some children show sensorimotor impairment, but these studies are very limited. Sensorimotor dysfunction could potentially arise from an imbalanced production of neurotransmitters that play a crucial role in motor control. Using the data obtained in the studies of several pathologies manifested by the association of sensory–motor dysfunction and intestinal dysbiosis, we attempt to substantiate the notion that malfunction of neurotransmitter production is caused by the imbalance of gut microbiota metabolites as a result of dysbiosis. This review delves into the exciting possibility of a connection between variations in the microbiome and ITW. The purpose of this review is to establish a strong theoretical foundation and highlight the benefits of further exploring the possible connection between alterations in the microbiome and TW for further studies of ITW etiology.

The recent outbreak of the novel coronavirus disease (COVID-19) has resulted in a huge num-ber of infected patients worldwide. This article provides a brief overview of the current state of the problem of the neurological consequences of COVID-19 caused by impaired neurogen-esis in the adult brain under the influence of the RNA-containing SARS‑CoV‑2 virus. The reported study was funded by RSF № 18-15-00392.

This work is based on the hypothesis of an impairment in neurogenesisduring aging, which may be one of the causes of neurodegenerativediseases, including Alzheimer’s disease (AD). Uncompensated neuronaldeath leads to memory loss. There is an opinion that activationof endogenous neurogenesis or cell replacement therapy may be aneffective treatment of AD. We used mesenchymal stromal cells (MSCs)isolated from the human umbilical cord Wharton’s jelly, which havea number of significant advantages over MSCs from other tissues.Human MSCs (hMSCs) were transplanted into the frontal cortex of8–9-month-old female 5XFAD transgenic (Tg) mice, a model of thehereditary AD. To evaluate the effects of such transplantation,spatial memory was analyzed in parallel with morphofunctional characteristicsof adult neurogenic niches—the subgranular zone (SGZ) of the hippocampaldentate gyrus and the subventricular zone (SVZ) of the lateral ventriclesof the brain, as well as the brain areas responsible for learningand memory—the temporal cortex and CA1/CA3 fields of the hippocampus,using immunohistochemistry for markers of cell proliferation (BrdU)and neuronal differentiation (nestin, doublecortin, β-3 tubulin,NeuN, MAP2, GFAP). 5XFAD Tg mice were characterized by an impairedSGZ/SVZ ratio of proliferative activity and a reduced neuronal densityin the cortex and hippocampus. The positive effect of hMSC treatmenton memory and neuronal as well as glial density in the temporalcortex and hippocampal regions manifested itself two months after transplantation.By that time, hMSCs were detected in the brain of Tg mice only.Both in Tg and non-transgenic (nTg) mice treated with hMSCs, thedensity of BrdU+ cells was increased in the adult neurogenic niches,however only in the hippocampus of Tg mice, there was a reducednumber of amyloid plaques and apoptotic cells, as well as an increaseddensity of synaptophysin-immunopositive (SyP+) cells. Thus, thepositive effect of hMSCs was manifested in the hippocampus of Tgmice, the structure remote from the frontal cortex, i.e. the transplantationsite. Overall, our data indicate a paracrine effect of hMSCs, aswell as the validity of the chimeric model and the promising useof MSC therapy in the treatment of AD.

Despite significant advances in modern medicine, effective therapeutics for Alzheimer’s disease (AD) treatment have not yet been found. Currently, the use of exosomes and microvesicles derived from mesenchymal stem cells (MSCs) has begun to be considered as one of the promising approaches to the therapy of this disease. Exosomes and microvesicles in comparison with MSCs have significant benefits such as nanometric size, inability to divide, lack of risks of immunogenicity, malignant transformation, and thrombosis. In this work, cytochalasin B–induced membrane vesicles (CIMVs) from MSCs isolated from the adipose tissue were obtained and characterized, and the possibility of their penetration into the brain after intranasal administration was studied. Preliminarily, MSCs were transduced with the recombinant replication-deficient lentivirus containing RFP gene. The study was carried out on a model of sporadic AD in olfactory bulbectomized (OBX) mice, demonstrating behavioral, biochemical, and morphological signs of neurodegenerative process of the Alzheimer’s type. Four hours after intranasal administration, presence of vesicles containing the fluorescent protein RFP was observed in the hippocampus and neocortex of OBX mice, i.e., in the brain areas most vulnerable to AD. It is assumed that microvesicles administrated intranasally can act as nanocontainers for target delivery of biologically active compounds present in MSCs, or even drugs to the brain regions affected by neurodegeneration, and are a promising therapeutic agent for the treatment of AD.

The pandemic caused by a new strain of the SARS-CoV-2 coronavirus has swept the whole world but effective methods for treating this severe pathology have not yet been created. It has now been established that a risk of a severe course of COVID-19 is not so much a patient's age itself, but so-called age-related diseases; the renin-angiotensin system (RAS) is directly or indirectly involved into their development. The SARS-CoV-19 virus interacts with one of the main regulatory elements of this system, ACE2, and disrupts the balance between the two RAS branches. This ultimately manifests itself in an increase in levels of angiotensin II, which, through binding to the angiotensin type 1 receptor (AT1R), causes a number of pathological conditions, including hypertension, atherosclerosis, and cardiovascular diseases, enhances cell proliferation, apoptosis, death of vascular endothelial cells, etc. This process has been described in many reviews by Russian and foreign authors. However, cells of innate and adaptive immunity are another less well-described but no less important target of angiotensin II. The consequences of this interaction are analyzed in detail in this review. With COVID-19, dendritic cells are activated, macrophage proliferation and neutrophil infiltration increase with further involvement of CD4-lymphocytes and other cellular elements of the adaptive immunity in this process. Hyperactivation of the immune system is accompanied with the release of a large amount of pro-inflammatory cytokines, which can lead to the occurrence of a cytokine storm. The picture is aggravated by the inhibitory effect produced by the virus itself on the synthesis of signaling interferons at initial stages in its internalization into the cell. A separate section in the review ad-dresses the problem how to predict a risk of a developing serious condition and search for its predictors by analyzing the state of the RAS and ratios of key cellular elements in the immune system. This is extremely important for making decisions concerning the amount of necessary medical care and strategies for subsequent treatment.

The paper discusses the use of direct chemical transformation of glial cells into neurons to solve the problems of neurodegenerative diseases. Original experimental data on the success-ful use of a conversion cocktail for astrocyte-neuronal conversion in a primary cell culture of the 5xFAD mouse hippocampus are presented.

Here, we found that functionally active mitochondria isolated from the brain of NMRI donor mice and administrated intranasally to recipient mice penetrated the brain structures in a dose-dependent manner. The injected mitochondria labeled with the MitoTracker Red localized in different brain regions, including the neocortex and hippocampus, which are responsible for memory and affected by degeneration in patients with Alzheimer's disease. In behavioral experiments, intranasal microinjections of brain mitochondria of native NMRI mice improved spatial memory in the olfactory bulbectomized (OBX) mice with Alzheimer’s type degeneration. Control OBX mice demonstrated loss of spatial memory tested in the Morris water maze. Immunocytochemical analysis revealed that allogeneic mitochondria colocalized with the markers of astrocytes and neurons in hippocampal cell culture. The results suggest that a non-invasive route intranasal administration of mitochondria may be a promising approach to the treatment of neurodegenerative diseases characterized, like Alzheimer's disease, by mitochondrial dysfunction.