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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Study of the pathophysiological role of nitric oxide and nitrative stress in brain: translational effects on the cleavage of the amyloid precursor protein in Alzheimer's disease and post-translational effects on fibrinogen in brain ischemia

Ill-Raga, Gerard 28 September 2010 (has links)
Nitric oxide (NO) is a neurotransmitter involved in memory processes. Currently, the only recognized physiological signalling pathway controlled by NO is the activation of guanylyl cyclase. In this thesis, we propose an alternative NO-signalling pathway that involves the Heme-regulated eukaryotic initiation factor-2a kinase (HRI) and eIF2a phosphorylation. We have found that the enzyme BACE1, a key protein in Alzheimer’s disease (AD), is controlled by this novel pathway. This pathway would be involved in the physiology of memory formation and learning processes. We have also studied how an external stress factor, the Herpes Simplex Virus 1, can disrupt this cascade leading to a pathological increase in BACE1 and amyloid ß-peptide (Aß) production. Aß aggregates forming fibrils that generate free radicals. These react with NO producing peroxynitrite, which contribute to AD progression. Since NO turns toxic when produced in a pro-oxidant environment we have also studied the effect of peroxynitrite in Stroke. / L’òxid nítric (NO) és un neurotransmissor involucrat en processos de memòria. Actualment, l’única cascada de senyalització fisiològica controlada per NO consisteix en l’activació de la guanilat ciclasa. En aquesta tesi, en proposem una d’alternativa que inclou la fosforilació de eIF2a per la Heme-regulated eukaryotic initiation factor-2a kinase (HRI). Hem mostrat com l’enzim BACE1, una proteïna clau en la malaltia d’Alzheimer (AD), és controlat per aquesta nova cascada de senyalització, que podria estar involucrada en la fisiologia de l’aprenentatge i la memòria. També hem estudiat com un factor d’estrès extern, l’ Herpes Simplex Virus 1, pot pertorbar aquesta cascada donant lloc a increments patològics en BACE1 i pèptid ß-amiloide (Aß). L’Aß agrega formant fibril·les que generen radicals lliures. Aquests reaccionen químicament amb NO produint peroxinitrit, que contribueix a la progressió de l’AD. Pel fet que l’NO esdevé tòxic quan és produït en un entorn pro-oxidant, hem estudiat també l’impacte que el peroxinitrit té en l’ictus.

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