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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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Primary structures of Aβ, IAPP and IAPP-GI (A) and tautomeric and protonation states of histidine side chain (B).1H-15N HSQC spectra of histidine side chains were acquired with coherence transfer from ε1H and δ2H to ε2N and δ1N through 2J coupling constants.
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pone-0020289-g001: Primary structures of Aβ, IAPP and IAPP-GI (A) and tautomeric and protonation states of histidine side chain (B).1H-15N HSQC spectra of histidine side chains were acquired with coherence transfer from ε1H and δ2H to ε2N and δ1N through 2J coupling constants.

Mentions: One approach to inhibit an aggregation reaction is to re-design the self-recognition interface of peptide or protein molecules, in a manner that the modified molecule is still capable of interacting with the native form, but inhibits its further assembly into larger aggregates [13]. This approach was successfully exploited for example in the case of Islet Amyloid Polypeptide (IAPP) [13], [14]. IAPP is a hydrophobic strongly amyloidogenic peptide, which is produced in the pancreatic islet cells and plays, in the soluble monomeric form, a major role in glucose homeostasis [15]. In certain circumstances, this peptide undergoes a transition from a predominantly random coil monomeric state to β-sheet aggregates, and these aggregates have been shown to be strongly toxic for several cell types and associated with the progressive destruction of pancreatic beta cells in adult-onset diabetes [16]. To keep the physiologic function of IAPP but block its amyloid forming propensity, an IAPP analogue was designed through the structure-based introduction of a minimum number of two N-methyl groups, at Gly24 and Ile26, located in the amyloid core and with side chains presumably pointing into a similar direction (see Figure 1A) [13], [17]. It was shown that the so-called IAPP-GI peptide efficiently inhibits IAPP amyloid formation and cytotoxicity [13], [17]. More interestingly, IAPP-GI was demonstrated to block cytotoxic assembly of Aβ and insulin as well [18], [19]. The cross-association reaction between IAPP-GI (or nonfibrillar IAPP conformers) and Aβ may have some implications beyond its therapeutic potentials, and along with clinical and epidemiological evidences, provide a potential molecular link between AD and adult-onset diabetes [20]. On a more general level and based on recent evidence for other cross-interactions between amyloidogenic polypeptides and proteins including the Aβ-tau and the Aβ-prion protein interaction, it appears that cross-amyloid interactions may play a critical role in neurodegenerative diseases [21], [22].


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)

Primary structures of Aβ, IAPP and IAPP-GI (A) and tautomeric and protonation states of histidine side chain (B).1H-15N HSQC spectra of histidine side chains were acquired with coherence transfer from ε1H and δ2H to ε2N and δ1N through 2J coupling constants.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3102090&req=5

pone-0020289-g001: Primary structures of Aβ, IAPP and IAPP-GI (A) and tautomeric and protonation states of histidine side chain (B).1H-15N HSQC spectra of histidine side chains were acquired with coherence transfer from ε1H and δ2H to ε2N and δ1N through 2J coupling constants.
Mentions: One approach to inhibit an aggregation reaction is to re-design the self-recognition interface of peptide or protein molecules, in a manner that the modified molecule is still capable of interacting with the native form, but inhibits its further assembly into larger aggregates [13]. This approach was successfully exploited for example in the case of Islet Amyloid Polypeptide (IAPP) [13], [14]. IAPP is a hydrophobic strongly amyloidogenic peptide, which is produced in the pancreatic islet cells and plays, in the soluble monomeric form, a major role in glucose homeostasis [15]. In certain circumstances, this peptide undergoes a transition from a predominantly random coil monomeric state to β-sheet aggregates, and these aggregates have been shown to be strongly toxic for several cell types and associated with the progressive destruction of pancreatic beta cells in adult-onset diabetes [16]. To keep the physiologic function of IAPP but block its amyloid forming propensity, an IAPP analogue was designed through the structure-based introduction of a minimum number of two N-methyl groups, at Gly24 and Ile26, located in the amyloid core and with side chains presumably pointing into a similar direction (see Figure 1A) [13], [17]. It was shown that the so-called IAPP-GI peptide efficiently inhibits IAPP amyloid formation and cytotoxicity [13], [17]. More interestingly, IAPP-GI was demonstrated to block cytotoxic assembly of Aβ and insulin as well [18], [19]. The cross-association reaction between IAPP-GI (or nonfibrillar IAPP conformers) and Aβ may have some implications beyond its therapeutic potentials, and along with clinical and epidemiological evidences, provide a potential molecular link between AD and adult-onset diabetes [20]. On a more general level and based on recent evidence for other cross-interactions between amyloidogenic polypeptides and proteins including the Aβ-tau and the Aβ-prion protein interaction, it appears that cross-amyloid interactions may play a critical role in neurodegenerative diseases [21], [22].

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