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Gen expresion of high affinity choline transporter in mouse model of Alzheimer's disease
Kurfürst, Helena ; Doležal, Vladimír (advisor) ; Krištofíková, Zdena (referee)
: Choline is being used in all mammalian cells as a precursor for synthesis of a major phospholipide phosphatidylcholine and as a donor of acetyl residues. Cholinergic neurons in addition require choline to synthesize neuromediator acetylcholine. The ability of cells to create choline via de novo synthesis is limited and therefore they need to transport choline from extracellular space. Limited availability of choline in brain leads specifically to diminished function of cholinergic neurons and in general to impaired reparation of biological membranes. Dysfunctions of cholinergic signaling in brain is characteristic for Alzheimer's disease. Aim of this work was to investigate whether gene and protein expression of high- affinity cholinergic transporters is altered in 5-6 months old APPswe/PS1dE9 mouse model of Alzheimer's disease. Expression of specific high-affinity cholinergic transporter CHT1 (responsible for transport of choline to be used for acetylcholine synthesis) and putative high-afinity choline transporter CTL1 (generally present in all cells and related to high affinity choline transport for phospholipide synthesis) in cerebral cortex was measured. Compared to non-trangenic littermates, no changes in the expression of both genes were detected at either mRNA (quantitative PCR) or protein...
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Cholinergic neurons and Alzheimer's disease
Machová, Eva ; Doležal, Vladimír (advisor) ; Krištofíková, Zdena (referee) ; Zvolský, Petr (referee)
Alzheimer's disease is a degenerative brain disorder. The incidence of the disease increases with age and every year the total number of affected persons is higher. The malfunction of various mental functions is a typical feature of Alzheimer's disease, including loss of short-term memory and development of personality changes. It is now generally accepted that the main cause of the disease is increased production of r3-amyloid fragments that mediate toxic effects and lead to r3-amyloid plaques formation. Alzheimer's disease and also normal aging are accompanied by a loss of cholinergic neurons and weakened cholinergic neurotransmission. In my thesis I dealt with changes in the brain chol inergic system during aging in control mice and in a mouse model of Alzheimer's disease (APPswe/PS1 dE9). In this context I also investigated in vitro influence of docosahexaenoic acid (w-3 essential fatty acid) changes in membrane cholesterol content on the expression of cholinergic phenotype in the NG108-1 5 cholinergic cell line. I also performed ex vivo experiments on rat brain cortex to investigate the characteristics of action of muscarin ic agonist xanomeline that was developed as a selective muscarinic agonist to strengthen signalization through the muscarinic M1 receptor in Alzheimer's disease. The experiments on...
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Mitochondrial protein 17β-hydroxysteroid dehydrogenase type 10 in the brain of a genetic animal model of Alzheimer's disease (McGill-R-Thy1-APP rats)
Hofmannová, Adéla ; Krištofíková, Zdena (advisor) ; Benek, Ondřej (referee)
Transgenic McGill-R-Thy1-APP rats are one of the best animal genetic models of Alzheimer's disease (AD). Significant intracellular elevation of soluble amyloid β (Aβ) and cognitive deficits are observed already in 3-month-old rats, prior to extracellular plaque deposition. Mitochondrial bioenergetic capacity appears to be altered via defects in complex I enzymatic activity in the electron transport chain already in 6-month-old rats. Nucleus-encoded mitochondrial matrix protein 17β-hydroxysteroid dehydrogenase type 10 (17βHSD10) operates via multiple enzymatic and non-enzymatic functions and is known as a binding partner of intracellular Aβ. In patients with AD, 17βHSD10 overexpression has been reported in brain and increased levels in cerebrospinal fluid. Cytoplasmic 17βHSD10 is imported via the PINK1-Parkin-TOM/TIM pathway into mitochondrial matrix, where it binds e.g. cyclophilin D (CypD) and prevents its translocation to the inner mitochondrial membrane. By this mechanism, 17βHSD10 can regulate the opening of the mitochondrial permeability transition pore mediated by CypD. It seems that accumulated mitochondrial Aβ may influence this regulation. In this study, we measured 17βHSD10 levels in mitochondria isolated from the brain of 11-month-old homozygous McGill-R Thy1-APP rats and we evaluated...
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Pharmacological animal model of Alzheimer's disease (rat model Samaritan) and mediator system of N-methyl-D-aspartate receptor and nitric oxide
Matušková, Hana ; Krištofíková, Zdena (advisor) ; Soukup, Ondřej (referee)
Alzheimer's disease is a neurodegenerative disorder with the highest prevalence in the population and for which we do not have a cure so far. The aim of this thesis was to test the mediator system of the N-methyl-D-aspartate receptor and nitric oxide in an animal model of sporadic form of Alzheimer's disease (Samaritan Alzheimer's Rat Model; Taconic Pharmaceuticals, USA). Then compare these results with changes in hippocampal cholinergic system and cognitive tests. The Samaritan rat model is based on the unilateral in vivo application of β-amyloid42 and the pro-oxidative substances (ferrous sulfate heptahydrate and L-buthionine-(S,R)-sulfoximine). Neurochemical methods included testing of the NR1/NR2A/NR2B subunits of the N-methyl-D-aspartate receptor and activity of nitric oxide synthases (neuronal, endothelial, inducible) in the cortex, in both cases in the right and left hemisphere separately. Our results show that Samaritan rats exhibited significant changes in expression of NR2A/NR2B subunits of the N-methyl-D-aspartate receptor and activity of inducible nitric oxide synthase in cortex compared to control rats. The results of glutamatergic system are consistent with changes in activity of cholinergic transporter and cognitive tests (Morris water maze and active allothetic place avoidance)....
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Cholinergic neurons and Alzheimer's disease
Machová, Eva ; Doležal, Vladimír (advisor) ; Krištofíková, Zdena (referee) ; Zvolský, Petr (referee)
Alzheimer's disease is a degenerative brain disorder. The incidence of the disease increases with age and every year the total number of affected persons is higher. The malfunction of various mental functions is a typical feature of Alzheimer's disease, including loss of short-term memory and development of personality changes. It is now generally accepted that the main cause of the disease is increased production of r3-amyloid fragments that mediate toxic effects and lead to r3-amyloid plaques formation. Alzheimer's disease and also normal aging are accompanied by a loss of cholinergic neurons and weakened cholinergic neurotransmission. In my thesis I dealt with changes in the brain chol inergic system during aging in control mice and in a mouse model of Alzheimer's disease (APPswe/PS1 dE9). In this context I also investigated in vitro influence of docosahexaenoic acid (w-3 essential fatty acid) changes in membrane cholesterol content on the expression of cholinergic phenotype in the NG108-1 5 cholinergic cell line. I also performed ex vivo experiments on rat brain cortex to investigate the characteristics of action of muscarin ic agonist xanomeline that was developed as a selective muscarinic agonist to strengthen signalization through the muscarinic M1 receptor in Alzheimer's disease. The experiments on...
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Gen expresion of high affinity choline transporter in mouse model of Alzheimer's disease
Kurfürst, Helena ; Krištofíková, Zdena (referee) ; Doležal, Vladimír (advisor)
: Choline is being used in all mammalian cells as a precursor for synthesis of a major phospholipide phosphatidylcholine and as a donor of acetyl residues. Cholinergic neurons in addition require choline to synthesize neuromediator acetylcholine. The ability of cells to create choline via de novo synthesis is limited and therefore they need to transport choline from extracellular space. Limited availability of choline in brain leads specifically to diminished function of cholinergic neurons and in general to impaired reparation of biological membranes. Dysfunctions of cholinergic signaling in brain is characteristic for Alzheimer's disease. Aim of this work was to investigate whether gene and protein expression of high- affinity cholinergic transporters is altered in 5-6 months old APPswe/PS1dE9 mouse model of Alzheimer's disease. Expression of specific high-affinity cholinergic transporter CHT1 (responsible for transport of choline to be used for acetylcholine synthesis) and putative high-afinity choline transporter CTL1 (generally present in all cells and related to high affinity choline transport for phospholipide synthesis) in cerebral cortex was measured. Compared to non-trangenic littermates, no changes in the expression of both genes were detected at either mRNA (quantitative PCR) or protein...
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