ABSTRACT
A common feature of neurodegenerative disorders, in particular Alzheimer's disease (AD), is a chronic neuroinflammation associated with aberrant neuroplasticity. Development of neuroinflammation affects efficacy of stem and progenitor cells proliferation, differentiation, migration, and integration of newborn cells into neural circuitry. However, precise mechanisms of neurogenesis alterations in neuroinflammation are not clear yet. It is well established that expression of NLRP3 inflammasomes in glial cells marks neuroinflammatory events, but less is known about contribution of NLRP3 to deregulation of neurogenesis within neurogenic niches and whether neural stem cells (NSCs), neural progenitor cells (NPCs) or immature neuroblasts may express inflammasomes in (patho)physiological conditions. Thus, we studied alterations of neurogenesis in rats with the AD model (intra-hippocampal injection of Aß1-42). We found that in Aß-affected brain, number of CD133+ cells was elevated after spatial training in the Morris water maze. The number of PSA-NCAM+ neuroblasts diminished by Aß injection was completely restored by subsequent spatial learning. Spatial training leads to elevated expression of NLRP3 inflammasomes in the SGZ (subgranular zones): CD133+ and PSA-NCAM+ cells started to express NLRP3 in sham-operated, but not AD rats. Taken together, our data suggest that expression of NLRP3 inflammasomes in CD133+ and PSA-NCAM+ cells may contribute to stimulation of adult neurogenesis in physiological conditions, whereas Alzheimer's type neurodegeneration abolishes stimuli-induced overexpression of NLRP3 within the SGZ neurogenic niche.
Subject(s)
Alzheimer Disease , Inflammasomes , Alzheimer Disease/metabolism , Animals , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Neurogenesis , Rats , Spatial LearningABSTRACT
Alzheimer's disease is characterized by the loss of neurons, the accumulation of intracellular neurofibrillary tangles and extracellular amyloid plaques in the brain. However, there are contradicting data on differences in neurogenesis at the onset of the disease or before the formation of amyloid plaques. As awareness of the importance of the pre-symptom phase in neurodegenerative diseases grows in the context of early diagnosis and pathogenesis, we analyzed the critical periods of adult hippocampal neurogenesis at an early stage under the action of soluble Ab1-42 beta-amyloid. The proliferation, migration and neuronal cells survival were evaluated in mice with an injection of soluble amyloid beta-oligomers. It was found that the injection of Ab1-42 oligomers causes a decrease in cell proliferation in the mouse hippocampus. Despite the preservation of the neuroblast pool in animals after beta-amyloid injection, the process of radial migration is disrupted, and an increase in apoptosis in the neurogenic niche was revealed. Thus, our results demonstrate damage of neurogenesis critical stages: the progenitor cells, neuroblast migration, the integration of immature neurons, and the survival of neurons under application of soluble beta-amyloid oligomers. The obtained data indicate decline in proliferation rate in the subgranular zone, that is accompanied by ectopic differentiation and disturbed migration, producing, apparently, abnormal neurons that have lower survival rates. That could lead to a decrease in mature neurons numbers and the number of cells in the granular layer of the dentate gyrus.
Subject(s)
Amyloid beta-Peptides/administration & dosage , Cell Proliferation , Hippocampus/drug effects , Neurogenesis/drug effects , Neurons/drug effects , Peptide Fragments/administration & dosage , Alzheimer Disease/pathology , Amyloid beta-Peptides/pharmacology , Animals , Apoptosis/drug effects , Cell Differentiation/drug effects , Cell Movement/drug effects , Cell Proliferation/drug effects , Disease Models, Animal , Hippocampus/pathology , Injections, Intraventricular , Male , Mice, Inbred Strains , Neurofibrillary Tangles/drug effects , Neurons/pathology , Peptide Fragments/pharmacology , Plaque, Amyloid/pathologyABSTRACT
The purpose of the study was to develop a battery of tests to study social and cognitive impairments for behavioral phenotyping of aging experimental animals with physiological neurodegeneration. Object of the study were outbred CD1 mice in the following groups: 1st group - 12-month old male mice (physiological aging); 2nd group - 2-month old male mice (control group). Social recognition test, elevated plus maze test (EPM), open field test, light-dark box test, and Fear conditioning protocol were used to estimate the neurological status of experimental animals. We found that aging male mice in a contrast to young ones have demonstrated lower social interest to female mice in the social recognition task. EPM and light-dark box tests showed increased level of anxiety in the group of aged mice comparing to the control group. Fear conditioning protocol revealed impairment of associative learning and memory in the group of aged mice, particularly, fear memory consolidation was dramatically suppressed. Analysis of behavioral factors, social interactions and anxiety level in the experimental mice has confirmed age-related neurodegeneration in the 1st group. We found that the most informative approach to identifying neurological impairments in aging mice (social interaction deficit, limitation of interests, increased level of anxiety) should be based on the open field test light-dark box test, and Fear conditioning protocol. Such combination allows obtaining new data on behavioral alterations in the age-associated of neurodegeneration and to develop novel therapeutic strategies for the treatment of age-related brain pathology.
Subject(s)
Aging/psychology , Behavior, Animal/physiology , Cognition Disorders/diagnosis , Social Behavior Disorders/diagnosis , Age Factors , Animals , Anxiety/diagnosis , Conditioning, Psychological , Fear/psychology , Female , Learning Disabilities/diagnosis , Male , Memory , Mice , Nervous System Diseases/diagnosisABSTRACT
The peculiarities in expression of transport proteins and the proteins implicated in the control of glycolysis by the cellular components of neurovascular units were examined in animals of different age under normal conditions and after modeled perinatal stress or hypoxic brain injury. In both cases, the specialties in expression of transport proteins in ontogenesis were revealed. The perinatal hypoxic brain injury resulted in up-regulation of MCT1, MCT4, and GLUT4 expression in endotheliocytes of hippocampal microvessels accompanied by transient elevation of HIF-1α and GSK3 expression.
Subject(s)
Anxiety, Separation/genetics , Glucose Transporter Type 4/genetics , Glycogen Synthase Kinase 3/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia/genetics , Stress, Psychological/genetics , Age Factors , Animals , Animals, Newborn , Anxiety, Separation/complications , Anxiety, Separation/metabolism , Anxiety, Separation/pathology , Astrocytes/metabolism , Astrocytes/pathology , Blood-Brain Barrier/metabolism , Blood-Brain Barrier/pathology , Endothelial Cells/metabolism , Endothelial Cells/pathology , Female , Gene Expression Regulation , Glucose Transporter Type 4/metabolism , Glycogen Synthase Kinase 3/metabolism , Hippocampus/blood supply , Hippocampus/metabolism , Hippocampus/pathology , Humans , Hypoxia/complications , Hypoxia/metabolism , Hypoxia/pathology , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Male , Microvessels/metabolism , Microvessels/pathology , Neurons/metabolism , Neurons/pathology , Neurovascular Coupling , Rats , Rats, Wistar , Stress, Psychological/complications , Stress, Psychological/metabolism , Stress, Psychological/pathologyABSTRACT
Formation and functional plasticity of the blood-brain barrier is associated with the molecular events that occur in the brain neurovascular unit in the embryonic and early postnatal development. To study the characteristics of barriergenesis under physiological conditions, as well as recovering from perinatal hypoxia and early life stress, we examined the expression of proteins of cerebral endothelial tight junctions (JAM, ZO1, CLDN5) in rats aged 7, 28 and 70 days of postnatal development (P7P70). Under physiological conditions, we have found that the number of endothelial cells expressing JAM, ZO1, CLDN5 slightly increases in the cortex, hippocampus and amygdala of the brain in the period from P7 to P70. Perinatal hypoxia significantly increased the number of cells expressing proteins of tight junction proteins (JAM, CLDN5) up to the age P28P70, whereas the number of cells expressing ZO1 was reduced in the same period of time. Early life stress led to an imbalance between the number of cells expressing ZO1 proteins and that expressing tight junctions proteins, but these changes were in opposite direction to that observed in perinatal hypoxia
Subject(s)
Cerebellum/metabolism , Endothelial Cells/metabolism , Gene Expression Regulation , Tight Junction Proteins/biosynthesis , Tight Junctions/metabolism , Animals , Cerebellum/cytology , Cerebellum/growth & development , Endothelial Cells/cytology , Female , Male , Rats , Rats, WistarABSTRACT
We studied in vitro development of brain progenitor cells isolated from healthy 7-9-month-old Wistar rats and rats with experimental Alzheimer's disease kept under standard conditions and in enriched (multistimulus) environment in vivo. Progenitor cells from healthy animals more rapidly formed neurospheres. Considerable changes at the early stages of in vitro development of brain progenitor cells were observed in both groups kept in enriched environment.
Subject(s)
Neural Stem Cells/physiology , Alzheimer Disease/pathology , Animals , Brain/pathology , Cell Proliferation , Cells, Cultured , Environment , Environment Design , Housing, Animal , Rats, WistarABSTRACT
The review covers current concepts on cell and molecular mechanisms of neuroinflammation and aging with the special focus on the regulation of cytokine-producing activity of astroglial cells and intercellular communication. The review reflects that a key component of the aging phenomenon as a result of ineffective implementation of anti-inflammatory response are processes of the dysregulated cytokine production, in particular, an increase in the secretion of proinflammatory cytokines and an imbalance in the expression of the receptors and receptor associated proteins. Interpretation of the molecular mechanisms of cell conjugating neuroinflammation and aging cells can give rise to new therapeutic strategies that are relevant to the treatment of a wide range of central nervous system diseases and the development of new experimental models of diseases of the central nervous system.
Subject(s)
Brain , Cellular Senescence , Central Nervous System Diseases , Inflammation/metabolism , Neurons/metabolism , Brain/physiology , Brain/physiopathology , Cell Communication , Central Nervous System Diseases/metabolism , Central Nervous System Diseases/physiopathology , Cytokines/metabolism , Humans , Models, NeurologicalABSTRACT
Therapy of rats with CCl4 hepatitis with Stellaria media L. water-soluble polysaccharide fraction in a dose of 100 mg/kg reduces serum activities of transaminases (ALT and AST), alkaline phosphatase, bilirubin, and the thymol test values. In the liver, the density of inflammatory infiltration of the organ parenchyma, total count of necrotic hepatocytes, fatty and protein degeneration are reducing. Hence, water-soluble polysaccharide fraction, isolated from the terrestrial part of Stellaria media L., is characterized by hepatoprotective activity.
