Design and Characterisation of Multifunctional Tools for the Elucidation of the Cu+ Chemistry in Alzheimer`s Disease

by Markus Rittmeier
Doctoral thesis
Date of Examination:2013-02-05
Date of issue:2013-09-06
Advisor:Prof. Dr. Franc Meyer
Referee:Prof. Dr. Franc Meyer
Referee:Prof. Dr. Ulf Diederichsen
Persistent Address: http://dx.doi.org/10.53846/goediss-4040

 

 

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Abstract

English

Alzheimer’s disease is the most common neurodegenerative disease in the world. Alzheimer’s disease is clinically characterised by decreased cognitive performance and pathologically characterised by formation of fibrillar amyloid plaques, so called Aβ-plaques and neurofibrillary tangles, which are aggregated tau proteins. It was first described by the German physician Alois Alzheimer in 1906. Even after 100 years, no therapies are available which can cure the disease or stop its progression. Current drugs only alleviate the symptoms and even this is strongly limited. Reason for the lack of effective drugs is that, to date, many questions remain unanswered. The exact biochemical processes which lead to the Aβ-plaques and to the cell death are not known. Since elevated levels of redox-active transition metals, primarily copper and iron, were found in the Aβ-plaques, evidence is provided that these processes are metal-mediated. Several biological markers indicate an increased oxidative stress in Alzheimer’s disease afflicted brain tissues, which could be induced by the enrichment of metals. In contrast to iron, which is associated with ferritin, copper is directly incorporated in the Aβ-plaques. Thus, an involvement of copper is more likely than of iron. A redox cycle was thus proposed which focuses on copper as the cause of increased oxidative stress. However, without an analytical tool which can intercept the cycle through coordination of intermediary formed Cu+, this and other hypotheses involving copper are yet to be unambiguously proven. The aim of this study is the synthesis and characterisation of such a tool. For the desired application a system is necessary which is not only selective for Cu+ but also targets the Aβ-plaques. This was achieved by the synthesis of a multifunctional compound consisting of two subunits, a Cu+-selective chelating moiety and one with a high affinity for Aβ-plaques. For the synthesis of the latter, dyes which can intercalate in the β-sheet structure of the Aβ-plaques were used as a basis. By combining modern drug design with inorganic aspects, a set of tripodal {NS2} and tetradentate {N2S2} ligands were synthesised and evaluated with respect to their metal binding properties. The systems with the best results with respect to affinity, selectivity, and stability, were then introduced into the multifunctional tool. Three multifunctional systems could be synthesised and first studies indicate that the compounds can be used for in vivo studies.
Keywords: Alzheimer’s Disease; Copper; Chelating; Amyloid plaques
 
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