Kinetics of Amyloid and Prion Fibril Formation in the Absence and Presence of Dense Shell Sugar-Decorated Dendrimers

Authors: F. Ottaviani, M.; Cangiotti, M.; Fiorani, L.; Fattori, A.; Wasiak, T.; Appelhans, D.; Klajnert, B.

Source: Current Medicinal Chemistry, Volume 19, Number 34, December 2012 , pp. 5907-5921(15)

Publisher: Bentham Science Publishers

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Abstract:

The aggregation behavior of the amyloid peptide Aβ1-28 and the prion peptide PrP185-208 - both responsible for neurodegenerative disorders – was analyzed in the absence and in the presence of poly(propylene imine) (PPI) dendrimers at generation 5 (G5) with a dense shell of maltose and maltotriose units. Thioflavin T (ThT) fluorescence assay and circular dichroism (CD) experiments indicated that fibril formation is enhanced at low dendrimer concentration, while it is prevented at relatively high dendrimer concentrations. Computer aided EPR analysis by means of the selected spin probe 4-octyl-dimethylammonium,2,2,6,6-tetramethyl-piperidine-1-oxyl bromide (CAT8) further demonstrated this behavior, but also provided detailed information on the mechanism of fibril formation and on the different behavior of the differently decorated dendrimers. The CAT8 radicals were progressively trapped at the peptide interphase when peptide aggregates were formed, also monitoring pre-fibrillar structures. At later time, a phase separation of the CAT8 radicals monitors the formation of further supramolecular structures where the probes become squeezed among fibrillar aggregates. The addition of small amounts of dendrimers promotes the formation of peptide fibrils breaking them and providing a larger amount of ends that serve as sites of replications. Conversely, a high amount of dendrimers allows the peptides to well separate from each other such preventing their aggregation. EPR results also indicate that the perturbation played by PPI(G5)-Maltose are more effective onto PrP185-208 than onto Aβ1-28, while PPI(G5)-Maltotriose is less effective towards PrP185-208 in both promoting aggregation and preventing it by changing the dendrimer concentration. These results provide useful information about the mechanism and interactions which regulate the ability of macromolecules like the dendrimers to favor, prevent or cure neurodegenerative diseases.

Keywords: Amyloid; CD; EPR; PPI; ThT; alzheimer; fluorescence; glyco-dendrimers; nitroxide; prion

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/092986712804143259

Publication date: December 1, 2012

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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