Aggregation and fibril formation of amyloid-beta peptides (A) are central events in the pathogenesis and progression of Alzheimer’s disease (AD). Aggregation of A is a complex process which involves the formation of several soluble intermediate species, including oligomeric and protofibrillar forms, and ends with the deposition of ordered fibrillar architectures. Considerable evidence suggests that soluble ordered oligomeric intermediates, rather than insoluble peptide deposits, exert cytotoxic effects and play a crucial role in AD onset and progression. A soluble intermediates therefore represent appealing targets for the design of new specific inhibitors potentially useful for AD treatment. Nevertheless the complexity of the aggregation process and the difficulty of obtaining a reproducible in vitro assay has hampered, in most cases, the detailed characterization of the mode of action of the newly designed compounds. Given the importance of these aspects for a further characterization of amyloid aggregation process as well as for the design of selective inhibitors, our objective was to develop a more comprehensive methodology to characterize the formation of A42 aggregates and their morphology. This objective has been achieved by combining a reproducible aggregation assay with a multi-methodological detection approach, which would allow the characterization of the different assembly species along the aggregation pathway. This approach includes both qualitative and quantitative methodologies such as atomic force resonance microscopy, ThT-based assays, mass spectrometry-based techniques, suitable for the characterization of the A42 aggregation. Obtained information is crucial to avoid confusing outcomes from aggregation studies and from inhibitor screening assays, thus helping the design of new effective drugs for the treatment of AD. In this light, this multi-methodological approach was applied to the characterization of the mode of inhibition of myricetin, a well known natural polyphenol which was reported to act as inhibitor of A aggregation. The developed analytical approach provided a clearer and more consistent picture of the in vitro A42 aggregation process, by detailing the diverse assembly species which are formed from the early stages to fibrilization. The same approach can be generally extended to the aggregation of many other aggregation-prone peptides involved in several human aggregation diseases.

A MULTI-METHODOLOGICAL APPROACH FOR BETA-AMYLOID AGGREGATION AND INHIBITION STUDIES

BARTOLINI, MANUELA;NALDI, MARINA;FIORI, JESSICA;ANDRISANO, VINCENZA
2010

Abstract

Aggregation and fibril formation of amyloid-beta peptides (A) are central events in the pathogenesis and progression of Alzheimer’s disease (AD). Aggregation of A is a complex process which involves the formation of several soluble intermediate species, including oligomeric and protofibrillar forms, and ends with the deposition of ordered fibrillar architectures. Considerable evidence suggests that soluble ordered oligomeric intermediates, rather than insoluble peptide deposits, exert cytotoxic effects and play a crucial role in AD onset and progression. A soluble intermediates therefore represent appealing targets for the design of new specific inhibitors potentially useful for AD treatment. Nevertheless the complexity of the aggregation process and the difficulty of obtaining a reproducible in vitro assay has hampered, in most cases, the detailed characterization of the mode of action of the newly designed compounds. Given the importance of these aspects for a further characterization of amyloid aggregation process as well as for the design of selective inhibitors, our objective was to develop a more comprehensive methodology to characterize the formation of A42 aggregates and their morphology. This objective has been achieved by combining a reproducible aggregation assay with a multi-methodological detection approach, which would allow the characterization of the different assembly species along the aggregation pathway. This approach includes both qualitative and quantitative methodologies such as atomic force resonance microscopy, ThT-based assays, mass spectrometry-based techniques, suitable for the characterization of the A42 aggregation. Obtained information is crucial to avoid confusing outcomes from aggregation studies and from inhibitor screening assays, thus helping the design of new effective drugs for the treatment of AD. In this light, this multi-methodological approach was applied to the characterization of the mode of inhibition of myricetin, a well known natural polyphenol which was reported to act as inhibitor of A aggregation. The developed analytical approach provided a clearer and more consistent picture of the in vitro A42 aggregation process, by detailing the diverse assembly species which are formed from the early stages to fibrilization. The same approach can be generally extended to the aggregation of many other aggregation-prone peptides involved in several human aggregation diseases.
XX National Meeting on Medicinal Chemistry - Book of Abstracts
74
74
Bartolini M.; Naldi M.; Fiori J.; Valle F.; Biscarini F.; Nicolau D.V.; Andrisano V.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/91837
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