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Dissertation zugänglich unter
URN: urn:nbn:de:gbv:18-56967
URL: http://ediss.sub.uni-hamburg.de/volltexte/2012/5696/


Characterization of proteins involved in the production of β-Amyloid peptides and tau hyperphosphorlation in Familial Alzheimer’s Disease

Charakterisierung von Proteinen, die an der Produktion von β-Amyloid Peptiden und Hyperphosphorylierung in Familiärem Alzheimer beteiligt sind

Barrera Ocampo, Alvaro Andres

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SWD-Schlagwörter: Alzheimer-Krankheit , Amyloid <beta-> , Tau-Protein , Gehirn , Demenz
Freie Schlagwörter (Deutsch): Amyloid vorläuferprotein, Presenilin, Prion Protein, GSK3beta, Erk
Freie Schlagwörter (Englisch): Amyloid precursor protein, Presenilin, Prion Protein, GSK3beta, Erk
Basisklassifikation: 44.00 , 42.13
Institut: Biologie
DDC-Sachgruppe: Biowissenschaften, Biologie
Dokumentart: Dissertation
Hauptberichter: Glatzel, Markus (Prof. Dr.)
Sprache: Englisch
Tag der mündlichen Prüfung: 25.05.2012
Erstellungsjahr: 2012
Publikationsdatum: 16.07.2012
Kurzfassung auf Englisch: Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease afflicting currently 35 million people worldwide. The two basic variants of AD are sporadic (SAD) and familial (FAD). SAD is characterized by absence of inheritance pattern, while FAD is characterized by autosomal dominant heritability and it is caused by genetic mutation in the genes coding for APP, PS1 or PS2. Mutations in PS1 cause the most severe forms of AD with an early onset of ~45 years. More than 390 families carrying PS1 mutations have been identified, including the worldwide largest group of individuals bearing a missense PS1 mutation consisting of around 5000 members of a Colombian kindred carrying the E280A mutation. The most important pathological hallmarks of AD are senile plaques and neurofibrillary tangles (NFTs). The first are extracellular aggregates of Aβ peptides produced by the proteolytic processing of APP made by secretases, and the latter are intracellular aggregates of hyperphosphorylated Tau protein as consequence of altered activity of Tau-protein kinases.

The main goal of this work was to establish the expression profile of proteins involved in the production of Aβ and Tau hyperphosphorylation as potential biomarkers for different variants of AD. We have found that in FAD the expression of APP was altered as consequence of its increased processing. Although no major changes were observed in the expression profile of α- and β-secretases, variations in PS1 indicated that this protein is a determinant for the development of the disease in both AD variants. We also observed that in FAD the expression of PrPc was modified, while in SAD no changes were observed. The differential expression of this protein in FAD and SAD is another point of divergence between both forms of AD and may help to explain the dynamic of the Aβ accumulation and the production of Aβ plaques. In FAD the activation level of GSK3β was decreased in the analyzed areas, while in SAD the activation of this kinase was elevated. This activation profile indicates that the steady-state of this enzyme is regulated in a differential fashion in both AD forms. The activation profile of Erk1/2 was increased in both forms of AD. Based on these facts we propose that Erk1/2 may be involved in the hyperphosphorylation of Tau and the formation of NFTs in FAD and SAD, while GSK3β contributes to this process in SAD, but not in FAD.

Testican-1 is a novel molecule that seems to be involved in the pathogenesis of AD as seen in CSF of affected cases. We show that it associates with Aβ plaques and in vitro analysis revealed that Testican-1 decreases Aβ levels in HEK293T cells expressing the APP Swedish mutation. Further analysis showed that neither APP expression nor canonical processing was affected. Also, secretases and Aβ-degrading proteins were unaffected. However, subcellular localization of APP was altered by Testican-1 transfection and their subcellular localization modified. We conclude that this proteoglycan could regulate the β-secretase activity of cathepsin L and in this way modulate the production of Aβ. The results generated from this study can be used to create new methodologies for diagnosis and eventually treatment of the disease.

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