Structural characterization of amyloid beta oligomers with functional links associated to alzheimer’s disease
- Autores: Eduar Puig Gomà Camps
- Directores de la Tesis: Jesús García Arroyo (dir. tes.), Natalia Carulla (dir. tes.), Modesto Orozco López (tut. tes.)
- Lectura: En la Universitat de Barcelona ( España ) en 2019
- Idioma: español
- Tribunal Calificador de la Tesis: Antoni Riera Escalé (presid.), Marina Gay Marín (secret.), Justin L. P. Benesch (voc.)
- Programa de doctorado: Programa de Doctorado en Química Orgánica por la Universidad de Barcelona
- Materias:
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- Resumen
Alzheimer’s disease (AD) is the most common form of dementia. It was first described in 1906 by Alois Alzheimer. Later on, in 1984 George Glenner and Colin Masters isolated the amyloid-beta (Aβ) peptide from a human brain and associated it to the disease. Since then the amyloid hypothesis has been a rather controversial matter discussed among the scientific community. A possible explanation is the high complexity of the target due to the variety of aggregation forms that Aβ can adopt. Therefore, understanding the links between protein aggregation and neurotoxicity, and specially obtaining the 3D structures of the aggregates responsible for neurotoxicity is key to design effective diagnostic and therapeutic strategies. Unfortunately, this remains one of the most important unresolved issues in the field. The group of Dr. Carulla has been working on the hypothesis that Aβ interacts with the cell membrane leading to ionic dyshomeostasis. In order to study this scenario, the group has changed the paradigm and treated Aβ as a membrane protein and applied well known methodologies used to characterize this family of proteins to study Aβ. By doing so, the group has proved that Aβ is able to form a type of oligomer in the presence of detergent micelles which adopts a very specific and defined structure with characteristics of a β-barrel assembly and functions as a pore. They refer to these type of oligomer as β-Barrel Pore-Forming Oligomer (βPFO). Hereby we present the work carried out to identify by using different biophysical techniques, the 3D structure of βPFO. we have used detergents to study the oligomerization process in a membrane mimetic environment. Micelles compared to other more native-like biomimetics environments based on lipids, will enable the application of novel mass spectrometry (MS) strategies and well-established solution NMR techniques thus providing high-resolution structural information. Since the accumulation of different amounts of Aβ in the membrane is a plausible scenario in the context of the disease, we have used different Aβ to detergent micelle ratios ([Aβ]:[M]) to study the role of this variable in the oligomerization process of Aβ.
