Immunocytochemical Characterization of Alzheimer’s Disease Hallmarks in APP/PS1 Transgenic Mice Treated with a New Anti-Amyloid-β Vaccine

Introduction: APP/PS1 double-transgenic mouse models of Alzheimer’s disease (AD), which overexpress mutated forms of the gene for the human amyloid precursor protein (APP) and presenilin 1 (PS1), have provided robust neuropathological hallmarks of an AD-like pattern at early ages. This study aimed to characterize immunocytochemical patterns of the AD mouse brain, which is treated with the EB101 vaccine, as a model for human AD.Material and methods: In this novel vaccine, a new approach has been taken to circumvent past failures with A? vaccines by judiciously selecting an adjuvant consisting of a physiological matrix embedded in liposomes, composed of naturally occurring phospholipids (phosphatidylcholine, phosphatidylglycerol, and cholesterol).Results: Our findings showed that the administration of amyloid-?1?42 (A?) and sphingosine-1-phosphate emulsified in liposome complex (EB101) to APP/PS1 mice before the onset of A? brain deposition (at 7 weeks of age) and/or at an older age (35 weeks of age) can be effective in both halting the progression and clearing the AD-like neuropathological hallmarks. In addition, passive immunization with EB101 did not activate inflammatory responses from the immune system and astrocytes. Consistent with a decreased inflammatory background, the basal immunological interaction between the T cells and the affected areas (hippocampus) in the brain of treated mice was notably reduced.Conclusion: These results provide strong evidence that immunization with the EB101 vaccine prevents and attenuates AD neuropathology in this type of double-transgenic mice

Metagenomic analysis of gut microbial communities from a Central Asian population

OBJECTIVE: Changes in the gut microbiota are increasingly recognised to be involved in many diseases. This ecosystem is known to be shaped by many factors, including climate, geography, host nutrition, lifestyle and medication. Thus, knowledge of varying populations with different habits is important for a better understanding of the microbiome. DESIGN: We therefore conducted a metagenomic analysis of intestinal microbiota from Kazakh donors, recruiting 84 subjects, including male and female healthy subjects and metabolic syndrome (MetS) patients aged 25-75 years, from the Kazakh administrative centre, Astana. We characterise and describe these microbiomes, the first deep-sequencing cohort from Central Asia, in comparison with a global dataset (832 individuals from five countries on three continents), and explore correlations between microbiota, clinical and laboratory parameters as well as with nutritional data from Food Frequency Questionnaires. RESULTS: We observe that Kazakh microbiomes are relatively different from both European and East Asian counterparts, though similar to other Central Asian microbiomes, with the most striking difference being significantly more samples falling within the Prevotella-rich enterotype, potentially reflecting regional diet and lifestyle. We show that this enterotype designation remains stable within an individual over time in 82% of cases. We further observe gut microbiome features that distinguish MetS patients from controls (eg, significantly reduced Firmicutes to Bacteroidetes ratio, Bifidobacteria and Subdoligranulum, alongside increased Prevotella), though these overlap little with previously published reports and thus may reflect idiosyncrasies of the present cohort. CONCLUSION: Taken together, this exploratory study describes gut microbiome data from an understudied population, providing a starting point for further comparative work on biogeography and research on widespread diseases. TRIAL REGISTRATION NUMBER: ISRCTN37346212; Post-results

СОВРЕМЕННОЕ ПРЕДСТАВЛЕНИЕ О МОЛЕКУЛЯРНО-ГЕНЕТИЧЕСКИХ МАРКЕРАХ РАКА ПРЕДСТАТЕЛЬНОЙ ЖЕЛЕЗЫ

Purpose of the study: to present up-to-date data on molecular genetic studies aimed to identify the risks of developing prostate cancer in representatives of various ethnic groups. Material and Methods. Literary sources were searched in databases such as PubMed, Medline, Google Scholar. We had analyzed 60 sources on the risks of developing prostate cancer. The epidemiological data on the prostate cancer incidence and risk factors depending on age characteristics, hormonal status and hereditary predisposition were shown. Results. The pathogenetic features of prostate cancer depending on ethnicity were described. The paper presents data from both European and Asian ethnic groups. In a number of studies, significant genetic differences in single nucleotide polymorphisms associated with the development of prostate cancer were identified. Conclusion. Research in the field of determining the risks of developing prostate cancer becomes more and more relevant due to the emergence of new molecular genetic markers, as well as the influence of various ethnic characteristics. Nevertheless, many questions of modern diagnosis of prostate cancer are still open, therefore, research in this area remains promising. Цель исследования – представить современные данные молекулярно-генетических исследований, посвященных выявлению рисков развития рака предстательной железы у представителей различных этнических групп.Материал и методы. Выполнен поиск литературных источников, доступных в базах данных PubMed, Medline, Google Scholar. Нами было проанализировано 52 источника, посвященных рискам развития рака предстательной железы. Приведены эпидемиологические данные по распространенности изучаемой патологии в мире, а также детально продемонстрированы факторы риска в зависимости от возрастных особенностей, гормонального статуса и наследственной предрасположенности.Результаты. Освещены патогенетические особенности рака предстательной железы в зависимости от этнической принадлежности. В работе представлены данные как европейской, так и азиатской этнических групп. В ряде исследований описаны существенные генетические различия в однонуклеотидных полиморфизмах, ассоциированных с развитием рака предстательной железы.Заключение. Исследования в области определения рисков развития рака предстательной железы с каждым годом становятся все перспективнее благодаря появлению новых молекулярно-генетических маркеров, а также изучению различных этнических особенностей. Тем не менее остаются открытыми многие вопросы современной диагностики рака предстательной железы, поэтому исследования в данной области являются актуальными.

SNPS ASSOCIATED WITH MYOCARDIUM REMODELING IN HYPERTENSION IN THE KAZAKH POPULATION

Introduction: Cardiovascular Disease (CVD) is the leading cause of mortality in Kazakhstan. Among all CVDs, hypertension is the most common and leads to remodeling of myocardium, which significantly increases cardiovascular risk. Some studies have been carried out to elucidate the genetic markers associated with target organ damage in hypertension, but not in Kazakh population. The aim of this study is to find out SNPs associated with myocardium remodeling in Kazakh population. Materials and methods: The sample size is 500 people There were 2groups of 250 hypertensive individuals, age - up to 61years. 1. Group without remodeling 2. with myocardial remodeling (MR) LVMI ≥115 in men, ≥95 in women, relative wall thickness ≥0.43 Clinical, laboratory, instrumental data were gathered. Рeripheral blood was taken for genotyping for SNPs known by association with target organ remodeling in HTN based on GWAS Catalog - EMBL-EBI and Varsome Clinical and PubMed publications. Genotyping was made using QuantStudio 12K Flex Real-Time PCR System by array technology. Results: Out of SNPs, seven SNPs were associated with myocardium remodeling. rs17016480 OR=1.80 (1.07-3.02) p=0.029, rs923109* OR=0.45 (0.20-1.03) p=0.033, rs11646213 OR=1.69 (1.14-2.53) p=0.009, rs113296370 OR=1,14 (0,68-1,93) p=0.036, rs591044 OR=0,49 (0,27-0,87) p=0.0095, rs2407103 OR=2.04 (1.18-3.52) p=0.011rs7016717 OR=3,74 (1.20-11.67) p=0.026 * marked polymorphisms associated with myocardium remodeling, but differing from the Hardy-Weinberg inheritance equilibrium in the control group

Age-Related Defects in Erythrocyte 2,3-Diphosphoglycerate Metabolism in Dementia

Alzheimer disease (AD) is the most common dementing illness. Metabolic defects in the brain with aging contribute to the pathogenesis of AD. These changes can be found systematically and thus can be used as potential biomarkers. Erythrocytes (RBCs) are passive reporter cells that are not well studied in AD. In the present study, we analyzed an array of glycolytic and related enzymes and intermediates in RBCs from patients with AD and non-Alzheimer dementia (NA), age-matched controls (AC) and young adult controls (YC). AD is characterized by higher activities of hexokinase, phosphofructokinase, and bisphosphoglycerate mutase and bisphosphoglycerate phosphatase in RBCs. In our study, we observed that glycolytic and related enzymes displayed significantly lower activities in AC. However, similar or significantly higher activities were observed in AD and NA groups as compared to YC group. 2,3-diphosphoglycerate (2,3-DPG) levels were significantly decreased in AD and NA patients. The pattern of changes between groups in the above indices strongly correlates with each other. Collectively, our data suggested that AD and NA patients are associated with chronic disturbance of 2,3-DPG metabolism in RBCs. These defects may play a pivotal role in physiological processes, which predispose elderly subjects to AD and NA

Immunocytochemical Characterization of Alzheimer Disease Hallmarks in APP/PS1 Transgenic Mice Treated with a New Anti-Amyloid-β Vaccine

APP/PS1 double-transgenic mouse models of Alzheimer’s disease (AD), which overexpress mutated forms of the gene for human amyloid precursor protein (APP) and presenilin 1 (PS1), have provided robust neuropathological hallmarks of AD-like pattern at early ages. This study characterizes immunocytochemical patterns of AD mouse brain as a model for human AD treated with the EB101 vaccine. In this novel vaccine, a new approach has been taken to circumvent past failures by judiciously selecting an adjuvant consisting of a physiological matrix embedded in liposomes, composed of naturally occurring phospholipids (phosphatidylcholine, phosphatidylglycerol, and cholesterol). Our findings showed that administration of amyloid-β1−42 (Aβ) and sphingosine-1-phosphate emulsified in liposome complex (EB101) to APP/PS1 mice before onset of Aβ deposition (7 weeks of age) and/or at an older age (35 weeks of age) is effective in halting the progression and clearing the AD-like neuropathological hallmarks. Passive immunization with EB101 did not activate inflammatory responses from the immune system and astrocytes. Consistent with a decreased inflammatory background, the basal immunological interaction between the T cells and the affected areas (hippocampus) in the brain of treated mice was notably reduced. These results demonstrate that immunization with EB101 vaccine prevents and attenuates AD neuropathology in this type of double-transgenic mice

Immunocytochemical Characterization of Alzheimer’s Disease Hallmarks in APP/PS1 Transgenic Mice Treated with a New Anti-Amyloid-β Vaccine

Introduction: APP/PS1 double-transgenic mouse models of Alzheimer’s disease (AD), which overexpress mutated forms of the gene for the human amyloid precursor protein (APP) and presenilin 1 (PS1), have provided robust neuropathological hallmarks of an AD-like pattern at early ages. This study aimed to characterize immunocytochemical patterns of the AD mouse brain, which is treated with the EB101 vaccine, as a model for human AD. Material and methods: In this novel vaccine, a new approach has been taken to circumvent past failures with Aβ vaccines by judiciously selecting an adjuvant consisting of a physiological matrix embedded in liposomes, composed of naturally occurring phospholipids (phosphatidylcholine, phosphatidylglycerol, and cholesterol). Results: Our findings showed that the administration of amyloid-β1−42 (Aβ) and sphingosine-1-phosphate emulsified in liposome complex (EB101) to APP/PS1 mice before the onset of Aβ brain deposition (at 7 weeks of age) and/or at an older age (35 weeks of age) can be effective in both halting the progression and clearing the AD-like neuropathological hallmarks. In addition, passive immunization with EB101 did not activate inflammatory responses from the immune system and astrocytes. Consistent with a decreased inflammatory background, the basal immunological interaction between the T cells and the affected areas (hippocampus) in the brain of treated mice was notably reduced. Conclusion: These results provide strong evidence that immunization with the EB101 vaccine prevents and attenuates AD neuropathology in this type of double-transgenic mice

Oxidative Stress Mediated Mitochondrial and Vascular Lesions as Markers in the Pathogenesis of Alzheimer Disease

Mitochondrial dysfunction plausibly underlies the aging-associated brain degeneration. Mitochondria play a pivotal role in cellular bioenergetics and cell-survival. Oxidative stress consequent to chronic hypoperfusion induces mitochondrial damage, which is implicated as the primary cause of cerebrovascular accidents (CVA) mediated Alzheimer\u27s disease (AD). The mitochondrial function deteriorates with aging, and the mitochondrial damage correlates with increased intracellular production of oxidants and pro-oxidants. The prolonged oxidative stress and the resultant hypoperfusion in the brain tissues stimulate the expression of nitric oxide synthase (NOS) enzymes, which further drives the formation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The ROS and RNS collectively contributes to the dysfunction of the blood-brain barrier (BBB) and damage to the brain parenchymal cells. Delineating the molecular mechanisms of these processes may provide clues for the novel therapeutic targets for CVA and AD patients