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Mechanisms of comorbidity of metabolic and neurodegenerative diseases
Tauchman, Martin ; Telenský, Petr (advisor) ; Brožka, Hana (referee)
In Czechia, number of people with neurodegenerative diseases is in the hundreds of thousands, and the lifetime health care costs and social impact of each patient's disease reach hundreds of thousands of euros, but these costs could be reduced by early and effective intervention. Its correct implementation could be helped by knowledge of causal links between neurodegenerative and metabolic diseases, whose prevalence is correlated in the population. One of the important factors is an increased pro-inflammatory immune response. In people with obesity and type 2 diabetes mellitus, systemic inflammation evolves into neuroinflammation, which subsequently leads to neurodegeneration. Another mechanism is hyperglycaemia, which is a consequence of insulin resistance. Hyperinsulinaemia and hyperglycaemia lead to impaired expression of glucose transporters and insulin-degrading enzyme, resulting in reduced clearance of amyloid beta. Genetic background is also recognized as a highly influential factor, affecting various mechanisms in both beneficial and harmful ways. Lifestyle is also an important factor. In general, smoking and alcohol consumption are harmful to health. Both increased consumption of alcoholic beverages and smoking tobacco products can lead to metabolic disorders as well as neurodegeneration. On the...
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Alkaloids of Dicranostigma franchetianum (Prain) Fedde and their selected biological activity
Wijaya, Viriyanata ; Opletal, Lubomír (advisor) ; Šmejkal, Karel (referee) ; Klouček, Pavel (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacognosy and Pharmaceutical Botany Candidate: Viriyanata Wijaya, M.Sc. Supervisor: Prof. RNDr. Lubomír Opletal, CSc. Title of Doctoral Thesis: Alkaloids of Dicranostigma franchetianum (Prain) Fedde and their selected biological activity Dicranostigma franchetianum (Prain) Fedde (Papaveraceae) is one of the representatives of the small genus Dicranostigma Hook. f. & Thomson. D. franchetianum (Prain) Fedde has been selected for the phytochemical investigation according to the screening study. In the primary screening of the alkaloid extract for cholinesterases inhibition, the inhibitory value was high (hAChE/hBChE, IC50 g/ml; 1.67 0.11 and 3.85 0.31) and together at least 15 alkaloids were found in the extract. The primary ethanol extract was prepared from 11.8 kg of dry herb (Garden of Medicinal Plants, Faculty of Pharmacy in Hradec Kralove). Using common chromatographic methods, 21 isoquinoline alkaloids of various structural types were isolated. All compounds have been identified using various spectrometric techniques (GC-MS, HPLC- MS, and 1D- and 2D-NMR, optical rotatory. The alkaloids obtained in sufficient amounts were determined for human acetylcholinesterase (hAChE), human butyrylcholinesterase (hBChE), and...
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Effect of amyloid β on the function of endosomes and lysosomes
Tmějová, Monika ; Rudajev, Vladimír (advisor) ; Čočková, Zuzana (referee)
Alzheimer's disease is progressive neurodegenerative disease characterized by accumulation of amyloid β aggregates in brain tissue. Understanding the mechanisms of amyloid β pathogenesis and neuronal cell destruction is still not clear. The most toxic form of amyloid β are 42 aminoacids long oligomers that tends to cumulate and speed up disease progression. Membrane dynamics which affect protein degradation and recycling within the cell plays a criticale role in maintaining homeostasis. Vesicular trafficking plays fundamental role in balancing physiological level of amyloid β. Disruption of endolysosomal complex leads to cycle of disruptions within the cell which results in neuronal cell death. The main aim of this thesis was to look through different ways how amyloid β42 affects endolysosomal compartment. Results of our work confirmed toxic effect of amyloid on SH-SY5Y cell line and its ability to damage functions of lysosomes. We were not able to confirm amyloid β toxicity on endosomal function. Key words: amyloid β, Alzheimer disease, oligomers, plasma membrane, endocytosis, endosome, lysosome, neurotoxicity
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Altered morphology of white and grey matter in patients with Alzheimer disease and Schizophrenia on MRI
Lahutsina, Anastasiya ; Zach, Petr (advisor) ; Horáček, Jiří (referee) ; Němcová, Veronika (referee)
Cortical folding of the anterior cingulate cortex (ACC), particularly the cingulate (CS) and the paracingulate (PCS) sulci, represents a neurodevelopmental marker. Deviations in in utero development in schizophrenia can be traced using CS and PCS morphometry. In the present study, we measured the length of CS, PCS, and their segments on T1 MRI scans in 93 patients with first episode schizophrenia and 42 healthy controls. Besides the length, the frequency and the left-right asymmetry of CS/PCS were compared in patients and controls. Distribution of the CS and PCS morphotypes in patients was different from controls. Parcellated sulcal pattern CS3a in the left hemisphere was longer in patients (53.8 ± 25.7 mm vs. 32.7 ± 19.4 mm in controls, p < 0.05), while in CS3c it was reversed-longer in controls (52.5 ± 22.5 mm as opposed to 36.2 ± 12.9 mm, n.s. in patients). Non parcellated PCS in the right hemisphere were longer in patients compared to controls (19.4 ± 10.2 mm vs. 12.1 ± 12.4 mm, p < 0.001). Therefore, concurrent presence of PCS1 and CS1 in the left hemisphere and to some extent in the right hemisphere may be suggestive of a higher probability of schizophrenia. Measurement of an hippocampal area or volume is useful in clinical practice as a supportive aid for diagnosis of Alzheimer's disease....
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Mitophagy biomarkers in the continuum of Alzheimer's disease
Katonová, Alžbeta ; Veverová, Kateřina (advisor) ; Bohačiaková, Dáša (referee)
The findings of recent years have shown that impaired mitophagy is involved in the pathophysiology of Alzheimer's disease (AD) and other neurodegenerative diseases. Studies on brain biopsies of AD patients, cellular and animal models of AD show that age-dependent decline in mitophagy is a significant contributor to AD pathology, and that the levels of mitophagy proteins are altered. However, whether these changes are reflected in the biofluids of individuals with AD, and whether mitophagy proteins could be potential biomarkers of AD, is unknown.The aim of the diploma thesis was to compare the level of mitophagy markers in blood serum and cerebrospinal fluid (CSF) of patients in various stages of AD with cognitively healthy controls (CU) and determine its relationship to the degree of cognitive impairment and standard Alzheimer's biomarkers (amyloid beta (Ab42), total tau (T-tau) and tau phosphorylated at threonine 181 (P-tau181)). We have shown that mitophagy is impaired in individuals with AD, manifested by increased levels of PINK1 and BNIP3L (activators of mitophagy) and decreased levels of TFEB (master regulator of lysosomal biogenesis) compared to CU. Moreover, these changes were associated with more advanced AD pathology, manifested by increased AD biomarker positivity and cognitive...
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The role of cholesterol in the pathogenesis of Alzheimer's disease
Tax, Martin ; Rudajev, Vladimír (advisor) ; Randáková, Alena (referee)
Alzheimer's disease is a neurodegenerative disorder and the most common form of dementia affecting a significant part of the aging population. It seems that the main cause of this disease is the accumulation of amyloid β (Aβ). Cholesterol is an important component of plasma membranes where it is essential for proper synapse function. Changes in its concentration are considered to be a risk factor for the onset and development of Alzheimer's disease. Data show that this lipid has an effect on Aβ synthesis and also has a role in Aβ cytotoxicity where it may promote the negative properties of Aβ or on the contrary can be protective against them.
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The role of microglia and astrocytes in Alzheimer's disease
Pospíšilová, Eva ; Telenský, Petr (advisor) ; Svoboda, Jan (referee)
Alzheimer's disease is a neurodegenerative disease that affects the central nervous system and is characterized mainly by problems with memory abilities. With the more aging population, the number of patients with this disease is gradually increasing, so Alzheimer's disease research is becoming one of the main priorities of today's health care. Although the research has been going on for more than a century, the exact causes of the Alzheimer's disease are still unclear. For a long time, the main role was attributed to the pathology of amyloid β and tau protein, the basic pathophysiological features of this disease, but in recent years, it has become clear that microglia and astrocytes also play an important role. These glial cells affect the amount of amyloid β and the hyperphosphorylated tau protein, but they are also crucial for maintaining homeostasis of the central nervous system. Activation of microglia and astrocytes in Alzheimer's disease can lead to disruption of the physiological functions of these neuroglia, and thus to problems with the removal of amyloid and tau protein, but also to the induction of chronic neuroinflammation. This work aims to summarize and organize the basic knowledge about the role of microglia and astrocytes in Alzheimer's disease, while focusing mainly on their role...
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Disorders of brain energy metabolism in Alzheimer's and Parkinson's disease
Řezáčová, Adéla ; Telenský, Petr (advisor) ; Kolář, David (referee)
Alzheimer's and Parkinson's diseases belong to group of neurodegenerative diseases that affect not only the patients, but also their surroundings. Patients of those diseases gradually lose their neurons. Both disorders are typical for pathophysiological accumulation of proteins which affect the functioning of neurons and astrocytes. These disorders are also characterised by mitochondrial senescence and its damages which itself manifest by dysfunction of various complexes. Furthermore, in both diseases, there can be found insulin resistance, which leads to an insufficient insulin signalization. Both diseases are also accompanied by impaired metabolisms of amino acids. With Alzheimer's disease, there is significantly lowered metabolism of glucose, whereas with Parkinson's disease, there is not enough stimulation for action potential to proceed in dopaminergic neurons in substantia nigra. These impairments in Alzheimer's disease cause cognitive dysfunction, while with Parkinson's disease, these defects predominantly lead to complications with motor function. By studying energetic changes in presented diseases could bring more effective treatment.
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