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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 accumulation of iron and other metals in the pathophysiology of neurodegenerative diseases
Mašková, Jana ; Dušek, Petr (advisor) ; Vymazal, Josef (referee) ; Bártová, Petra (referee)
The role of metal accumulation in the pathophysiology of neurodegenerative diseases has been a hot topic in recent years due to the possibility of its treatment by chelating agents. Although the mechanisms of neurodegeneration are well known, the role of metal accumulation is still unclear. The main limitation are unsatisfactory methods for in vivo metal imaging; the most widely used technique is magnetic resonance imaging (MRI). Our aim was to assess the possibility of using transcranial sonography (TCS) in differential diagnosis of neurodegenerative diseases and to further explore the underlying factors of echogenicity. In the first study, using TCS fusion with MRI, we focused on location verification of the commonly assessed structures (substantia nigra and nucleus lentiformis) and exclusion of possible focal structural changes affecting the echogenicity in WD and PD patients. Moreover, obtained MRI were used for semi-quantitative comparison with TCS images. Although TCS has been confirmed to be highly beneficial in differential diagnosis of Wilson's disease and it should be recommended as a screening method for extrapyramidal patients with atypical course of the disease, the direct relationship between TCS and metal deposits could not be proven. The obtained results from the ultrasound fusion...
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The role of mitochondria in the pathogenesis
Marková, Lenka ; Doležal, Pavel (advisor) ; Verner, Zdeněk (referee)
This thesis is focused on the existing data referring to role of mitochondria in the pathogenesis of several important diseases. It introduces mitochondrial proteins, their role and metabolism, dysfunction of which is behind pathogenetic processes. The thesis also summarizes possible mitochondrial damage, its progress and consequences, which can lead to diseases or aggravate their process. It also pays attention to the role of mitochondria during oncogenesis as well as important neurodegenerative disorders such as Alzheimer's or Parkinson's disease, Charcot-Marie-Tooth disease, amyotrophic lateral sclerosis or autosomal dominant optic atrophy. The thesis mentions the role of disrupted mitochondrial dynamics in type 2 Diabetes. In conclusion the thesis mentions the role of mitochondria and their damage in relation to infection by the parasites Toxoplasma gondii and Trypanosoma cruzi.
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Influence of intestinal microbiota on development of neurodegenerative diseases
Hakenová, Kristina ; Valeš, Karel (advisor) ; Vodička, Martin (referee)
Aging is associated with natural biological changes, which result in a decrease in the functional capacity of the body, which is also accompanied by an increased incidence of inflammatory processes that contribute to the development of neurodegeneration. The intestinal microbiota and its interaction with the intestine and the central nervous system play a key role in maintaining the function of biological homeostatic systems at an older age. This opens the possibility of influencing or modifying human microbiota for the development of therapeutic strategies. Based on the analysis of stool samples by HPLC MS / MS, the study confirmed the effect of selected probiotics on the modification of metabolic pathways and the proper functioning of the microbiota per se. The greatest effects were observed on tyrosine metabolism, tryptophan metabolism, arachidonic acid metabolism and bile acid biosynthesis metabolism. A positive effect of selected probiotic bacteria was found in the memory component of cognitive functions. Significant improvements were observed in verbal learning and verbal memory. In subjects with mild cognitive impairment, the progression of cognitive deficit has been slowed. Significant improvement was also observed for executive functions. These findings were not followed by a subjective...
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Involvement of cellular signal systems controlled by small G-proteins in neuroregenerative processes
Dušek, Jakub ; Novotný, Jiří (advisor) ; Košek, Dalibor (referee)
G-proteins repeatedly seem as significant signal mediators according to actual "cellular signal during neuroregeneration" reviews. This thesis aimed to find out how much small G-proteins correlate with neural tissue regeneration and which molecular mechanisms induce the regeneration. The thesis mentions pathologies of nervous system which are caused by traumas or neurodegenerative diseases in wider social perspective. Pivotal part of the text describes principles of functioning for each small GTPase family and its involvement in nervous tissue repair. This thesis demonstrates crucial role of small GTPases in neuroregeneration and points to considerable therapeutic potential of these GTPases. Key words: neuroregeneration; small GTPase; small G-protein; Ras; signal systems; neurodegeneration
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Automated diagnosis of sleep disorders using wearable devices
Sigmund, Jan ; Mekyska, Jiří (referee) ; Mikulec, Marek (advisor)
Sleep disorders induce many negative repercussions. Furthermore, research about their connection to cognitive health is increasing in numbers. This thesis concerns detection of poor sleep quality via raw actigraphy data. Existing method for assessing sleep was selected, it’s performance was validated against polysomnography on 27 patients. Used algorithm defines sleep as the absence of change in arm angle. Resulting 81 % sensitivity, 62 % specificity and 78 % accuracy is different from the outcome in the pilot study. Two approaches, to determine sleep quality were used. Both are based on comparing sleep features – first, with National Sleep Foundation recommendations and second, with control group without sleep disorders (7 persons). The goal was to pinpoint the remaining 19 patients with diagnosis. The recommendation for SOL, WASO, NA>5 and SE had higher sensitivity (75 %), lower specificity (71 %) and identical accuracy (74 %). These approaches were then also tested on 7-day actigraphy, consisting of 27 subjects, that are presumed to have prodromal dementia with Lewy bodies. Same principle was applied to try to predict LBD and thereby address the link between sleep quality and neurodegeneration. This resulted in 86 % sensitivity, 38 % specificity and 63 % accuracy. With regard to achieving solid sensitivity in all cases and good accuracy this could be used to indicate sleep quality.
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Trimeric G protein-regulated signaling in neurodegenerative processes
Daňková, Karolína ; Novotný, Jiří (advisor) ; Weissová, Romana (referee)
Members of the large family of G proteins and their coupled receptors are involved in a variety of transduction processes the cell uses to respond to a received signal. Depending on their specific structure and function, they influence a wide range of effector molecules. A large body of research has shown that many neurodegenerative diseases have a negative impact on the signal pathways controlled by G proteins. Due to ageing population, neurodegenerative diseases are currently imposing a risk for growing numbers of people. The sequelae observed in the pathological development of such diseases include especially changes in membrane receptors representation or receptor uncoupling from G protein, which inhibits G subunits activation. The undesirable inhibition or over-stimulation of G proteins results in the increase or decrease in effector activity, which subsequently impacts the production of second messengers and the activity of subsequent members of the signal cascade. As a result, these alterations lead to an increase in intracellular concentration of Ca2+ ions, which then influence receptors responsible for excitotoxicity, and contribute to apoptosis and necrosis of neuronal population. The thesis summarizes the defects of signalling pathways controlled by trimeric G proteins in association...
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The role of accumulation of iron and other metals in the pathophysiology of neurodegenerative diseases
Mašková, Jana ; Dušek, Petr (advisor) ; Vymazal, Josef (referee) ; Bártová, Petra (referee)
The role of metal accumulation in the pathophysiology of neurodegenerative diseases has been a hot topic in recent years due to the possibility of its treatment by chelating agents. Although the mechanisms of neurodegeneration are well known, the role of metal accumulation is still unclear. The main limitation are unsatisfactory methods for in vivo metal imaging; the most widely used technique is magnetic resonance imaging (MRI). Our aim was to assess the possibility of using transcranial sonography (TCS) in differential diagnosis of neurodegenerative diseases and to further explore the underlying factors of echogenicity. In the first study, using TCS fusion with MRI, we focused on location verification of the commonly assessed structures (substantia nigra and nucleus lentiformis) and exclusion of possible focal structural changes affecting the echogenicity in WD and PD patients. Moreover, obtained MRI were used for semi-quantitative comparison with TCS images. Although TCS has been confirmed to be highly beneficial in differential diagnosis of Wilson's disease and it should be recommended as a screening method for extrapyramidal patients with atypical course of the disease, the direct relationship between TCS and metal deposits could not be proven. The obtained results from the ultrasound fusion...
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The role of proteostatic mechanisms in neurodegenerative diseases
Zezulová, Kristýna ; Vodička, Petr (advisor) ; Marková, Vendula (referee)
Protein homeostasis (proteostasis) plays an important role in maintaining normal cell function and viability. Neurons are particularly vulnerable to proteostasis dysregulation, resulting in damage, dysfunction, and neuronal death, as manifested in many neurodegenerative diseases. One of them is Huntington disease, hereditary neurodegeneration with autosomal dominant inheritance. Expansion of the CAG repeats in the huntingtin gene is translated into an abnormally long glutamine chain in huntingtin protein, leading to disruption of neuronal proteostasis. The primary affected area of the brain is the striatum of the basal ganglia. Disease is progressive, the onset of symptoms usually occurs in adulthood, and after many years leads to the death of the patient. Despite intensive research, disease pathology is still not fully understood, treatment is still only symptomatic and new studies, together with a deeper understanding, also raise many new questions. Through the complexity of the issue, the study of proteostasis in neurodegeneration can bring not only possible implications for therapy, but also could go deeper into the understanding of stress, memory or aging processes.
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