Global ETD Search

1	Cellular level/distribution of -secretase subunit nicastrin and its modulator p23 in the brain Kodam, Anitha 06 1900 (has links) The processing of amyloid precursor protein (APP) by - and -secretases produces amyloid (A) peptide, the principal component of the neuritic plaques found in Alzheimers disease (AD) pathology. The enzyme -secretase is a multimeric protein consisting of presenilins-1/2 (PS1/PS2), nicastrin, anterior pharynx defective 1 (APH-1) and presenilin enhancer-2 (PEN-2). Recently it was discovered that p23, a transmembrane protein involved in intracellular protein trafficking, negatively regulates -secretase activity. In the present study, I evaluated the levels/expression of the nicastrin and p23 and their possible colocalization with PS1 in normal adult and developing brains. Additionally, I have studied the alterations of p23 levels in both animal model of neurodegeneration and in postmortem AD brains. Nicastrin and p23 were widely distributed throughout the brain and colocalized in all brain regions with PS1. The levels of nicastrin and p23 were relatively high at the early stages of postnatal development and then declined gradually as age increased. Interestingly, p23 level/expression was found to be altered following kainic acid-induced neurodegeneration in the adult rat brain. Additionally, p23 levels were reduced in the brains of individuals with AD. These results, taken together, suggest that both nicastrin and p23 are expressed in neurons throughout the brain and their levels decline gradually during development to reach an adult profile. Additionally, my results indicate that a decreased level of p23 may contribute to AD pathogenesis by increasing the production of A-related peptides. Nicastrin p23/TMP21 Gamma secretase Gamma secretase modulator Alzheimers disease
2	Cellular level/distribution of γ-secretase subunit nicastrin and its modulator p23 in the brain Kodam, Anitha Unknown Date No description available. Nicastrin p23/TMP21 Gamma secretase Gamma secretase modulator Alzheimer’s disease
3	Intramembrane proteolysis mediated by the gamma-secretase complex Nicastrin functions as a substrate receptor Shah, Sanjiv January 2006 (has links) Dissertation (Ph.D.) -- University of Texas Southwestern Medical Center at Dallas, 2006. / Vita. Bibliography: pp. 135-148.
4	Study of the pathophysiological role of nitric oxide on the amyloid-induced toxicity attending to the biochemical modifications and cellular damages Guix Ràfols, Francesc Xavier 22 January 2009 (has links) Aquesta tesi demostra que el peroxinitrit produït com a conseqüència del pèptid beta-amiloide (A) contribueix l'augment de la relació A42/A40 que ocorre a la malaltia d'Alzheimer. L'A42 contribueix a l'aparició de la malaltia degut a la seva major toxicitat (quan es compara amb l'A40) que resulta d'una gran estabilitat i capacitat agregativa. A més el peroxinitrit incrementa la toxicitat d'aquest degut a què potencia la seva agregació en forma d'oligomers altament tòxics. De fet els oligomers formats de nitro-A42 presenten una major toxicitat que aquells formats de A42 . En conjunt aquest resultats senyalen l'important paper que l'A42 té en la malaltia d'Alzheimer. Per altra banda, des de la identificació dels agregats d'A i la subseqüent formació dels cabdells neurofibrilars (NFT) com a els dos trets distintius de la malaltia, un gran esforç s'ha dedicat a establir els mecanismes moleculars que uneixen ambdós processos. Aquesta tesi demostra que el peroxinitrit format a partir de l'agregació de d'Ai la conseqüent nitrotirosinació de proteïnes, potencia l'agregació de la proteïna tau en forma de fibres. D'aquesta forma, la nitrotirosinació de la proteïna triosafosfat isomerasa (TPI) podria ser el vincle entre la toxicitat derivada del agregats d'Ai la patologia derivada de la proteïna tau. Per tant, la nitrotirosinació de la TPI podria explicar la progressió temporal que ocorre als cervells de pacients amb la malaltia d'Alzheimer des de la toxicitat induïda per l'Ai l'aparició dels NFT. Els resultats presentats en aquesta tesi podrien obrir nous aspectes en la recerca de la malaltia d'Alzheimer així com en altres malalties que cursin amb estrès oxidatiu i plegament erroni de proteïnes. / This thesis demonstrates that amyloid ß-peptide (Aß)-induced peroxynitrite contributes to the switch of the Aβ42/Aβ40 ratio that occurs in Alzheimer's disease (AD). Since Aβ42 is more toxic due to its higher aggregation and stability, it contributes to the trigger of the disease. In addition the aggregation of Aβ42 in form of the highly toxic oligomers is incremented by the presence of peroxynitrite. Moreover, these nitro-Aß42 oligomers are more toxic than those non-nitrated. All these results support the important role of peroxynitrite in AD etiology. Furthermore, since the identification of Aß accumulation and the subsequent formation of neurofibrillary tangles (NFT) as the two defining pathological hallmarks of AD, a fair amount of research on AD has been driven by the need to find the molecular mechanism linking Aß and NFT. This thesis shows the Aß-induced peroxynitrite, and the consequent nitrotyrosination of proteins, promotes tau fibrillization. Thus triosephosphate isomerase (TPI) nitrotyrosination could be the link between Aß-induced toxicity and tau pathology. Therefore, TPI nitrotyrosination may explain the temporal progression from Aß toxicity to NFT formation in AD brain. The work presented in this thesis could open a novel angle in the research of the pathophysiology of AD and could also have an impact to the research in other neurodegenerative diseases involving oxidative stress and protein misfolding. GAP free radicals fibrils familiar AD DHAP cerebral cortex BACE1 APH-1 antioxidants amyloid-beta peptide protein amyloid precursor alzheimer's disease advanced glycation end products acetylcholine plaques peroxinitrite peròxid d'hidrogen pèptid beta-amiloide Pen2 òxid nítric sintasa òxid nítric oligomers nitrotirosinasa nicastrina neurona metilglioxal malaltia d'alzheimer hipocamp glioxalase glicolisis GAP helicoidals aparellats filaments fibriles èstres oxidatiu DHAP cortex cerebral cabdells neurofibrilars BACE1 APH-1 antioxidants anió superòxid AD familiar AD esporàdic acetilcolina glycolysis glyoxalase hippocampus hydrogen peroxide methylglyoxal neurofibrillary tangles neuron nicastrin nitric oxide nitric oxide synthase nitrotyrosination oligomers oxidative stress pair helical filaments 616.8

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