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Vytvoření a charakterizace transgenních linií drozofil manifestující neurodegenerativní onemocnění spinocerebelární ataxi typu 1 (SCA1)
JIČÍNSKÁ, Veronika
The aim of this thesis was to generate and characterize transgenic lines of Drosophila melanogaster manifesting spinocerebellar ataxia type 1 (SCA1), using GAL4/UAS system. Specific driver lines were used to express ataxin gene in pan neuronal, eye and motor neurons. Adult males from different crosses expressing abnormal ataxin gene with parallel controls aged 5 day and 30 day were used for all experiments. The effects of such expression on mobility, longevity and neurodegenerative changes in the brain was studied. Moreover, specific techniques such are RT-PCR, and western blotting were used to test expression of specific genes and to quantify level of specific proteins. Neurodegenerative changes in transgenic lines were documented using confocal microscopy. The expression of specific genes such as ataxin and matrix metalloproteinase 1 and 2 (dMMP1, dMMP2) was studied in all used fly lines. The results showed that gene expression of hAtXN1 was higher in lines manifesting SCA1 compared to controls. However, the trend of MMP expression was not completely clear and will be the subject of future research.
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Neuroprotective effects of novel anorexigenic analogs of prolactin-releasing peptide (PrRP) in models of neurodegeneration in vitro and in vivo
Mengr, Anna ; Maletínská, Lenka (advisor) ; Sumová, Alena (referee) ; Hampl, Aleš (referee)
Alzheimer's disease (AD) is a progressive brain disorder characterized by extracellular beta amyloid (Aβ) plaques, intracellular neurofibrillary tangles formed by hyperphosphorylated Tau protein and neuroinflammation. Since obesity and type 2 diabetes mellitus (T2DM) have been established as risk factors for the development of neurological disorders, anorexigenic and antidiabetic peptides, such as prolactin-releasing peptide (PrRP) seem to be potential neuroprotective agents. In the first part of the study, the molecular mechanisms of action of natural PrRP31 and its lipidized analog palm11 -PrRP31 was studied in the human neuroblastoma cell line SH-SY5Y. Both compounds significantly activated the signaling pathways typical for insulin promoting cell survival and growth. Moreover, PrRP31 and palm11 -PrRP31 increased cell viability and suppressed apoptosis in methylglyoxal-stressed SH-SY5Y cells. The second part of the thesis was focused on the neuroprotective and anti-inflammatory effects of 2-month-long subcutaneous administration of palm11 -PrRP31 in the brains of APP/PS1 mice, model of Aβ pathology. Palm11 -PrRP31 significantly reduced the Aβ plaque load and microgliosis in the hippocampi, cortices, and cerebella. Furthermore, palm11 -PrRP31 increased the synaptogenesis and attenuated...
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The effect of physical activity on human psyche and cognitive functions
Štětka, Martin ; Hora, Martin (advisor) ; Novák, Jan (referee)
In modern society, absence of physical activity is often related not only to physical problems (e.g. the development of cardiovascular disease, diabetes, cancer, etc.) but also to mental problems (e.g. depression, anxiety and mood changes) and cognitive problems (e.g. learning, memory and motor problems), which are associated with the development of neurodegenerative diseases. Physical activity appears to be an effective regulator of proper brain ageing and may serve as a preventive measure against the development of many diseases. Individuals who actively engage in physical activity show a slower rate of brain atrophy in advanced age. In addition to regulating proper aging, physical activity can act as a supportive therapeutic tool in the treatment of various psychological problems. This bachelor thesis also discusses neurogenesis, neurodegeneration, evolutionary perspective, types of individual movements, change in mental status after induction of physical activity and development of cognitive abilities of individuals. Keywords: neurogenesis, neurodegeneration, aerobic exercise, anaerobic exercise, depression, anxiety, learning, memory
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Study of mechanisms influencing inflammatory and neurodegenerative processes and their subsequent treatment in ALS and spinal cord injury
Vargová, Ingrid ; Jendelová, Pavla (advisor) ; Jiruška, Přemysl (referee) ; Balaštík, Martin (referee)
Study of mechanisms influencing inflammatory and neurodegenerative processes and their subsequent treatment in models of ALS and spinal cord injury The mechanisms of neurodegeneration during spinal cord injury (SCI) and amyotrophic lateral sclerosis (ALS) are complex and poorly understood, which is why it's troublesome to counteract them with effective therapies. This thesis explores the pathways of autophagy, endoplasmic reticulum (ER) stress, and the mammalian target of rapamycin (mTOR) pathway that regulates these mechanisms in models of both SCI and ALS. Upregulation of autophagy and the mTOR pathway in an in vivo contusion SCI injury model was confirmed. The mTOR inhibition led to upregulation of autophagy, reduction of inflammation, and recovery in acute SCI. Upregulated autophagy was discovered in the SOD1G93A rat model of ALS. By treating the ALS rats with human mesenchymal stem cells, prolonged survival of the animals and preservation of motor neurons (MNs) possibly occurred through modulation of autophagy. The involvement of the mTOR pathway in the degeneration of MNs was further explored in the context of astrocytes. Pleckstrin homology like domain family A member 3 (PHLDA3), a newly discovered repressor of the mTOR pathway, was found to lead to ER stress if overexpressed in astrocytes...
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Tracking the progression of Alzheimer's like-pathology in transgenic rat model TgF344-AD
Foltýnová, Alice ; Telenský, Petr (advisor) ; Němec, Pavel (referee)
Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting dominantly the elderly and it is the most common cause of dementia. AD is characterized by many pathological events such as amyloid plaques, neurofibrillary tangles, inflammation, neurotransmitter dysregulation and many others. These disruptive processes ultimately lead to synaptic and cell loss which human brain. According to literaure, cell loss in AD is apparent especially in the cortex and hippocampus. However, it is unclear at which timepoint the loss becomes significant and in which other structures. There are many other important structures such as olfactory bulbs or entorhinal cortex where the cell loss has not been fully quantified. With new methods like isotropic fractionator it has become possible for scientists to quantify large number of structures more quickly. Since human brains are not easy to obtain shortly after death, use of transgenic animal models, mostly rodents, is a good way to obtain more information about cell and especially neuronal loss occurring in AD. Key words: Alzheimer's disease, cell loss, isotropic fractionator, hippocampus, neurofibrillary tangles, beta amyloid
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The role of aquaporins in the Alzheimer's disease
Kubísková, Monika ; Turečková, Jana (advisor) ; Vlachová, Viktorie (referee)
Alzheimer's disease (AD) is a progressive neurodegenerative disorder with complex pathophysiology affecting the central nervous system (CNS). In progress of the disease, various pathological changes occur in the brain, leading to neurodegeneration and subsequent impairment of physiological and cognitive functions. Although it is the most common cause of dementia in elderly, currently, there is no effective treatment for AD that that targets its underlying mechanisms. There are different theories as to which process is the key trigger for the development of AD. The generally accepted theory considers increased production of amyloid β (Aβ), its accumulation in the ECS and the formation of amyloid plaques as the main cause of the disease. However, recent studies show that the primary cause of amyloid plaque formation is not increased Aβ production, but rather its impaired clearance through the glymphatic system, the main component of which are aquaporin water channels, specifically aquaporin-4 (AQP4). The goal of this thesis is to provide an overview of the available knowledge on the involvement of aquaporins in AD pathophysiology, with a particular focus on AQP4 and its role in the glymphatic system. Key words: Alzheimer's disease, neurodegeneration, central nervous system, astrocytes, aquaporins,...
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The role of neuroinflammation in neurodegenerative CNS disease processes
Červenák, Karol ; Novotný, Jiří (advisor) ; Spišská, Veronika (referee)
Inflammatory processes in the CNS are an important element in neuroimmunity. They may be beneficial and have a neuroprotective effect but depending on the extent and duration of their activation they may also have a negative effect on the function of the CNS. Neuroinflammation is characterized by the activation of resident immune cells, microglia and astrocytes, activation of inflammatory signal pathways, recruitment of immune cells from the blood and their penetration through the blood-brain barrier. Chronic neuroinflammation may cause neurodegeneration and is key in the pathogenesis of neurodegenerative diseases. Neurodegeneration is irreversible but it can be mitigated. Therapeutic methods aimed at the modulation of neuroinflammation present a promising option for slowing down or stopping neurodegeneration for people with diseases such as Alzheimer's, Parkinson's, or Huntington's disease. The aim of this thesis is to sum up information about inflammatory processes in the brain and our current knowledge about their role in the pathogenesis of some neurodegenerative diseases. Key words: Inflammation, microglia, neurodegeneration, Alzheimer's disease, Parkinson's disease, Huntington's disease, CNS
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The role of endothelin receptors type A and B in the model of focal cerebral ischemia in immature rats
Vondráková, Kateřina ; Tsenov, Grygoriy (advisor) ; Říčný, Jan (referee)
Hypoxic-ischemic insult is a most common form of perinatal brain damage that threatens a newborn's life and can leads to permanent neurological sequelae. However, detailed aspects of the cerebral ischemia in the immature brain stay unanswered. We decide to use the model of focal cerebral ischemia induced by intrahippocampal endothelin-1 (ET-1) in 12-days-old rats. The knowledge about consequences of ET-1 induced ischemia and the role of endothelin receptors (ETA and ETB) in ischemia-induced consequences in immature brain are poor at present. Agonists and selective antagonists of the ETA and ETB receptors were used to determine the role of these receptors in the development of ischemia, changes in regional blood flow and tissue oxygenation, local changes of biochemical parameters and acute neuronal death. Our results indicates, that activation of the ETA receptors causes a strong decrease of the blood flow, induced related hypoxia and subsequent neuronal degeneration, whereas activation of ETB receptors has likely modulatory role. Moreover, ischemia causes increase of excitatory amino acids concentration, whereas inhibitory amino acid, except taurine, decreased after ischemia. These facts provides new insights in a case of perinatal ischemia. This thesis demonstrates the wide range of different effects of...
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Beneficial Effects of 11β-HSD1 Inhibition on Cognitive Performance in a Mouse Model of Alzheimer's Disease
Červinková, Tereza ; Červený, Lukáš (advisor) ; Musílek, Kamil (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Candidate: Tereza Červinková Supervisor: PharmDr. Lukáš Červený, Ph.D. Title: Beneficial Effects of 11β-HSD1 Inhibition on Cognitive Performance in a Mouse Model of Alzheimer's Disease The increased life expectancy goes hand in hand with ageing-related cognitive impairments. Alzheimer's disease (AD) is the most common type of dementia being an irreversible and progressive brain disorder with loss of cognitive functions. Recent studies suggest that excess of glucocorticoid (GC) action exerts deleterious effects on the hippocampus and causes impaired spatialmemory. In addition, it has been demonstrated that aged mice with cognitive deficits show increased gene expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in the hippocampus and parietal cortex. The Senescence-Accelerated Mouse Prone 8 (SAMP8) strain is a spontaneous animal model of accelerated ageing. Many studies indicate that SAMP8 harbour the behavioural and histopathological signatures of AD. In the present study, we evaluated the neuroprotective effects of 11β-HSD1 inhibition by a potent pyrrolidine-based compound RL-118 and/or effects of diet on cognitive performance in different groups of SAMP8 by conducting behavioural and...
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The role of nitric oxide during in pathophysiology of neurodegenerative diseases
Sikora Marečková, Věra ; Otáhal, Jakub (advisor) ; Konopková, Renata (referee)
Title: The role of nitric oxide in the pathophysiology of neurodegenerative diseases Objectives: The main objective of this thesis is to evaluate the effect of nitric oxide on the formation and development of neurodegenerative diseases. Another objective was to determinate, whether NO affects by its impact processes involved in apoptosis in the CNS. Methods: The thesis is prepared in the form of research, drawing from available relevant resources. Results: Nitric oxide is widely applied in the pathophysiology of selected neurodegenerative diseases, either directly or through other reactive nitrogen and oxygen. It also affects other factors that are involved in apoptosis in the CNS. Keywords: Nitric oxide, NMDA receptors, neurodegenerative diseases, excitotoxicity, apoptosis
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