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Interaction between amyloid beta peptide and an aggregation blocker peptide mimicking islet amyloid polypeptide.

Rezaei-Ghaleh N, Andreetto E, Yan LM, Kapurniotu A, Zweckstetter M - PLoS ONE (2011)

Bottom Line: The most pronounced NMR chemical shift changes were observed for residues 13-20, while residues 7-9, 15-16 as well as the C-terminal half of Aβ--that is both regions of the Aβ sequence that are converted into β-strands in amyloid fibrils--were less accessible to solvent in the presence of IAPP-GI.At the same time, interaction of IAPP-GI with Aβ resulted in a concentration-dependent co-aggregation of Aβ and IAPP-GI that was enhanced for the more aggregation prone Aβ42 peptide.On the basis of the reduced toxicity of the Aβ peptide in the presence of IAPP-GI, our data are consistent with the suggestion that IAPP-GI redirects Aβ into nontoxic "off-pathway" aggregates.

View Article: PubMed Central - PubMed

Affiliation: Department for NMR-based Structural Biology, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany.

ABSTRACT
Assembly of amyloid-beta peptide (Aβ) into cytotoxic oligomeric and fibrillar aggregates is believed to be a major pathologic event in Alzheimer's disease (AD) and interfering with Aβ aggregation is an important strategy in the development of novel therapeutic approaches. Prior studies have shown that the double N-methylated analogue of islet amyloid polypeptide (IAPP) IAPP-GI, which is a conformationally constrained IAPP analogue mimicking a non-amyloidogenic IAPP conformation, is capable of blocking cytotoxic self-assembly of Aβ. Here we investigate the interaction of IAPP-GI with Aβ40 and Aβ42 using NMR spectroscopy. The most pronounced NMR chemical shift changes were observed for residues 13-20, while residues 7-9, 15-16 as well as the C-terminal half of Aβ--that is both regions of the Aβ sequence that are converted into β-strands in amyloid fibrils--were less accessible to solvent in the presence of IAPP-GI. At the same time, interaction of IAPP-GI with Aβ resulted in a concentration-dependent co-aggregation of Aβ and IAPP-GI that was enhanced for the more aggregation prone Aβ42 peptide. On the basis of the reduced toxicity of the Aβ peptide in the presence of IAPP-GI, our data are consistent with the suggestion that IAPP-GI redirects Aβ into nontoxic "off-pathway" aggregates.

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Average backbone N and HN chemical shift perturbation in Aβ42 upon addition of IAPP-GI.The values are reported as slope of the best fitted line to chemical shift difference vs IAPP-GI concentration data, in units of ppm/M.
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pone-0020289-g005: Average backbone N and HN chemical shift perturbation in Aβ42 upon addition of IAPP-GI.The values are reported as slope of the best fitted line to chemical shift difference vs IAPP-GI concentration data, in units of ppm/M.

Mentions: Besides the uniform decrease in NMR signal intensity, several residues showed small changes in their N and HN chemical shifts after addition of IAPP-GI, while no significant chemical shift perturbation was found in the control experiments (Figure 3B). The strongest chemical shift changes were observed in a stretch of the peptide extending from His13 to Phe20, with additional perturbations appearing at residues Arg5, Ser8 and Asp23 (Figure 4A). Moreover, chemical shift changes of most of the peaks followed a linear relationship up to a molar ratio of IAPP-GI∶Aβ40 of 16∶1, with the largest linear slopes observed for residues His13-Lys16 (Figure 4B). Similar chemical shift changes were observed upon addition of IAPP-GI to Aβ42 (Figure 5). The gradual change in chemical shifts, the absence of new peaks and the lack of any site-specific broadening effect during the titration, suggests that the interaction between the two peptides occurs in the fast exchange regime on the NMR time scale and that the affinity of IAPP-GI to bind Aβ is relatively weak at the conditions of the NMR experiment.


Interaction between amyloid beta peptide and an aggregation blocker peptide mimicking islet amyloid polypeptide.

Rezaei-Ghaleh N, Andreetto E, Yan LM, Kapurniotu A, Zweckstetter M - PLoS ONE (2011)

Average backbone N and HN chemical shift perturbation in Aβ42 upon addition of IAPP-GI.The values are reported as slope of the best fitted line to chemical shift difference vs IAPP-GI concentration data, in units of ppm/M.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3102090&req=5

pone-0020289-g005: Average backbone N and HN chemical shift perturbation in Aβ42 upon addition of IAPP-GI.The values are reported as slope of the best fitted line to chemical shift difference vs IAPP-GI concentration data, in units of ppm/M.
Mentions: Besides the uniform decrease in NMR signal intensity, several residues showed small changes in their N and HN chemical shifts after addition of IAPP-GI, while no significant chemical shift perturbation was found in the control experiments (Figure 3B). The strongest chemical shift changes were observed in a stretch of the peptide extending from His13 to Phe20, with additional perturbations appearing at residues Arg5, Ser8 and Asp23 (Figure 4A). Moreover, chemical shift changes of most of the peaks followed a linear relationship up to a molar ratio of IAPP-GI∶Aβ40 of 16∶1, with the largest linear slopes observed for residues His13-Lys16 (Figure 4B). Similar chemical shift changes were observed upon addition of IAPP-GI to Aβ42 (Figure 5). The gradual change in chemical shifts, the absence of new peaks and the lack of any site-specific broadening effect during the titration, suggests that the interaction between the two peptides occurs in the fast exchange regime on the NMR time scale and that the affinity of IAPP-GI to bind Aβ is relatively weak at the conditions of the NMR experiment.

Bottom Line: The most pronounced NMR chemical shift changes were observed for residues 13-20, while residues 7-9, 15-16 as well as the C-terminal half of Aβ--that is both regions of the Aβ sequence that are converted into β-strands in amyloid fibrils--were less accessible to solvent in the presence of IAPP-GI.At the same time, interaction of IAPP-GI with Aβ resulted in a concentration-dependent co-aggregation of Aβ and IAPP-GI that was enhanced for the more aggregation prone Aβ42 peptide.On the basis of the reduced toxicity of the Aβ peptide in the presence of IAPP-GI, our data are consistent with the suggestion that IAPP-GI redirects Aβ into nontoxic "off-pathway" aggregates.

View Article: PubMed Central - PubMed

Affiliation: Department for NMR-based Structural Biology, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany.

ABSTRACT
Assembly of amyloid-beta peptide (Aβ) into cytotoxic oligomeric and fibrillar aggregates is believed to be a major pathologic event in Alzheimer's disease (AD) and interfering with Aβ aggregation is an important strategy in the development of novel therapeutic approaches. Prior studies have shown that the double N-methylated analogue of islet amyloid polypeptide (IAPP) IAPP-GI, which is a conformationally constrained IAPP analogue mimicking a non-amyloidogenic IAPP conformation, is capable of blocking cytotoxic self-assembly of Aβ. Here we investigate the interaction of IAPP-GI with Aβ40 and Aβ42 using NMR spectroscopy. The most pronounced NMR chemical shift changes were observed for residues 13-20, while residues 7-9, 15-16 as well as the C-terminal half of Aβ--that is both regions of the Aβ sequence that are converted into β-strands in amyloid fibrils--were less accessible to solvent in the presence of IAPP-GI. At the same time, interaction of IAPP-GI with Aβ resulted in a concentration-dependent co-aggregation of Aβ and IAPP-GI that was enhanced for the more aggregation prone Aβ42 peptide. On the basis of the reduced toxicity of the Aβ peptide in the presence of IAPP-GI, our data are consistent with the suggestion that IAPP-GI redirects Aβ into nontoxic "off-pathway" aggregates.

Show MeSH
Related in: MedlinePlus