A critical aspect to understanding the molecular basis of Alzheimer's disease (AD) is the characterization of the kinetics of interconversion between the different species present during amyloid-β protein (Aβ) aggregation. By monitoring hydrogen/deuterium exchange in Aβ fibrils using electrospray ionization mass spectrometry, we demonstrate that the Aβ molecules comprising the fibril continuously dissociate and reassociate, resulting in molecular recycling within the fibril population. Investigations on Aβ40 and Aβ42 amyloid fibrils reveal that molecules making up Aβ40 fibrils recycle to a much greater extent than those of Aβ42. By examining factors that could influence molecular recycling and by running simulations, we show that the rate constant for dissociation of molecules from the fibril (k(off)) is much greater for Aβ40 than that for Aβ42. Importantly, the k(off) values obtained for Aβ40 and Aβ42 reveal that recycling occurs on biologically relevant time scales. These results have implications for understanding the role of Aβ fibrils in neurotoxicity and for designing therapeutic strategies against AD.
An emerging and attractive target for the treatment of Alzheimer's disease is to inhibit the aggregation of beta-amyloid protein (Abeta). We applied the retro-enantio concept to design an N-methylated peptidic inhibitor of the Abeta42 aggregation process. This inhibitor, inrD, as well as the corresponding all-L (inL) and all-D (inD) analogues were assayed for inhibition of Abeta42 aggregation. They were also screened in neuroblastoma cell cultures to assess their capacity to inhibit Abeta42 cytotoxicity and evaluated for proteolytic stability. The results reveal that inrD and inD inhibit Abeta42 aggregation more effectively than inL, that inrD decreases Abeta42 cytotoxicity to a greater extent than inL and inD, and that as expected, both inD and inrD are stable to proteases. Based on these results, we propose that the retro-enantio approach should be considered in future designs of peptide inhibitors of protein aggregation.
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