Tesis doctoral de Teresa Muñoz De Galdeano
Alzheimer¿s disease (ad) is a neurodegenerative disease that appears under two forms: the late form or sporadic alzheimer disease (sad) and the early form or familial alzheimer disease (fad). The fad is a dominant autosomal disease caused by mutations in the app, ps-1 and ps-2 genes. On the other hand, the age is the risk factor better established for the ad and oxidative stress (os) associated is considered an earliest event for the disease. In order to investigate the effects, in the neuronal death and in the app metabolism/processing, produced by app mutations in the presence of os we generated stably transfected cellular lines of an human neuroblastoma expressing the wild type app and the ¿swedish¿ (km670/671nl) app. Our results, using the free radical generating system xanthine/xanthine oxidase, demonstrated that the app mutations sensitize the cells to the damage induced by the os. Also, we have studied the app metabolism/processing in our fad cellular model: the ¿swedish¿ app expression in combination with os. We found that the os alone regulates the app metabolism/processing, modulating the production of the amino terminal proteolytic fragment (soluble extracellular app, sapp¿) and of the intracellular carboxyl terminal fragments: ¿ctf (non amyloidogenic) and íYctf (amyloidogenic). Regarding the fad cellular model we found that the cellular response in the app metabolism/processing was altered. Corroborating, alterations related with os response in the mutant cellular line, the genomic study of the fad model revealed the overexpression of the heme oxygenase-1 (ho-1) gene, an enzyme related with the ad; finally, with the functional analysis using the novel technique of gene silencing, we found that the inhibition of the ho-1 expression, in the mutant cell line, increased the neuronal death by the os. The present results show a dynamic cellular model for the study of fad, whose altered mechanisms could serve as therapeutic target in the ad.
Datos académicos de la tesis doctoral «Aproximacion in vitro a los mecanismos patogenicos de la enfermedad de alzheimer genetica«
- Título de la tesis: Aproximacion in vitro a los mecanismos patogenicos de la enfermedad de alzheimer genetica
- Autor: Teresa Muñoz De Galdeano
- Universidad: Autónoma de Madrid
- Fecha de lectura de la tesis: 21/07/2010
Dirección y tribunal
- Director de la tesis
- Fernando Valdivieso Amate
- Tribunal
- Presidente del tribunal: federico Mayor menendez
- María Lopez de ceballos lafarga (vocal)
- eva Carro díaz (vocal)
- Alberto Lleo bisa (vocal)