Tesis doctoral de Anton Vladimirov Kichev
The aim of the present work is to investigate a possible relationship between the pro-form of the neurotrophic growth factor (pro-ngf) and the cell death induced during pathogenesis of alzheimer disease (ad). we studied the physiological effect of pro-ngf isolated from human brain (hbi-pro-ngf) in different cell models that express p75ntr. We show that hbi-pro-ngf is a potent pro-apoptotic agent. Interestingly, the hbi-pro-ngf isolated from control human brain was shown not to be able of inducing cell death in the models used. specific receptor of pro-ngf was described to be p75ntr. We describe that higher amounts of its processing products # p75ntr icd, are observed in brain tissue affected from ad. in the cellular models used by us, the induction of apoptosis was preceded by processing of p75ntr with liberation of its icd. P75ntr processing is γ-secretase dependent. The induction of pro-apoptotic effect was shown to be entirely dependent of γ-secretase activity. Released p75ntr icd is shown to be translocated to nuclei. Hbi-pro-ngf isolated from control brain is not able of inducing processing of p75ntr neither translocation of its icd. the levels of non enzymatic post-translational modifications of pro-ngf in the hippocampus and enthorinal cortex shows to increase in ad affected brains. This can explain the greater stability and elevated physiological activity of pro-ngf isolated from human brains affected with ad. the in vitro modified pro-ngf by glyoxal and methylglyoxal shows greater resistance against the furine cleavage and consequently greater ability to induce cell death trough p75ntr. Mice intracerebroventricularly injected with this modified rh-pro-ngf present significant learning difficulties compared with controls intracerebroventricularly injected with non modified pro-ngf and even greater differences compared with modified bsa. the results that we describe suggest the possibility that highest levels of non enzymatic modifications of pro-ngf in human brain during the progress of ad could lead to cell loss by activation of p75ntr by γ-secretase dependent activation.
Datos académicos de la tesis doctoral «Implication of pro-ngf in the neurodegeneration: characterization of the underlying physiological mechanisms in alzheimer¿s disease«
- Título de la tesis: Implication of pro-ngf in the neurodegeneration: characterization of the underlying physiological mechanisms in alzheimer¿s disease
- Autor: Anton Vladimirov Kichev
- Universidad: Lleida
- Fecha de lectura de la tesis: 01/12/2008
Dirección y tribunal
- Director de la tesis
- Carme Espinet Mestre
- Tribunal
- Presidente del tribunal: José enrique Esquerda colell
- isidro Ferrer abizanda (vocal)
- Jesús María no Ureña bares (vocal)
- María Lopez de ceballos lafarga (vocal)