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    Stabilization of secondary structure of synthetic Alzheimer beta-amyloid protein analogs in the presence of aluminum (III) ions

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    Author
    Vyas, Sandip Bipin
    Keyword
    Biochemistry
    Behavioral psychology
    Neurosciences
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    URI
    http://hdl.handle.net/11122/9451
    Abstract
    The gradual accretion of fibrillar protein deposits in a tissue or organ is a hallmark of all amyloidogenic diseases. These deposits accumulate as senile plaques and cerebrovascular deposits in the brain and are characteristics of Alzheimer's disease. A majority of the brain amyloid deposits consist of a 40 amino acid protein, the Alzheimer $\beta$-protein, A$\beta$P, which in a soluble form is ubiquitous in biological tissues. In order to provide a more detailed understanding of the structural transformations of soluble A$\beta$P, sequence analogs derived from $\beta$1-40, and having His $\to$ Arg, and scL-Asp- $\to$ scD-Asp substitutions were synthesized. The kinetic variations of $\beta$1-40 and $\beta$6-25 were studied using amide circular dichroism spectroscopy by monitoring ellipticity changes of the peptide backbone. In both peptides, the gradual loss of secondary structure was a multiphasic process which was also dependent on concentration. The circular dichroism titrations with metal ions revealed the involvement of at least two ions in the conformational transitions of $\beta$1-40 and $\beta$6-25. The association of Al(III) with scL-Asp $\to$ scD-Asp derived analogs caused surprising conformational changes in $\beta$6-25, which were distinct from $\beta$1-40. Microheterogeneous products corresponding to Al(III)-bound peptide species were resolvable on the reversed-phase surface. The association of aluminum was investigated by low field $\sp{27}$Al nuclear magnetic resonance spectroscopy. The signal corresponding to Al(III)-bound peptide species revealed that at least four Al(III) ions were bound to $\beta$1-40 and $\beta$6-25 between pH 5 and 6. Moreover, $\beta$1-40 effectively competed with EDTA to bind with Al(III). This study also describes a strategy which resolved the band broadening in reversed-phase high-performance liquid chromatography of $\beta$1-40 and derived analogs. Chromatographic parameters related to interactive contact area of $\beta$1-40 and derived analogs were determined on reversed-phase matrix. The peptides were bound to the reversed-phase surface in their monomeric form. Slow partition kinetics appear to contribute to significant band broadening, which suggests a secondary retention effect--indicating a conformational change due to unfolding on the stationary phase surface.
    Description
    Dissertation (Ph.D.) University of Alaska Fairbanks, 1995
    Date
    1995
    Type
    Dissertation
    Collections
    Chemistry and Biochemistry

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