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Formation of dynamic soluble surfactant-induced amyloid ? peptide aggregation intermediates.

ABSTRACT: Intermediate amyloidogenic states along the amyloid ? peptide (A?) aggregation pathway have been shown to be linked to neurotoxicity. To shed more light on the different structures that may arise during A? aggregation, we here investigate surfactant-induced A? aggregation. This process leads to co-aggregates featuring a ?-structure motif that is characteristic for mature amyloid-like structures. Surfactants induce secondary structure in A? in a concentration-dependent manner, from predominantly random coil at low surfactant concentration, via ?-structure to the fully formed ?-helical state at high surfactant concentration. The ?-rich state is the most aggregation-prone as monitored by thioflavin T fluorescence. Small angle x-ray scattering reveals initial globular structures of surfactant-A? co-aggregated oligomers and formation of elongated fibrils during a slow aggregation process. Alongside this slow (minutes to hours time scale) fibrillation process, much faster dynamic exchange (k(ex) ?1100 s(-1)) takes place between free and co-aggregate-bound peptide. The two hydrophobic segments of the peptide are directly involved in the chemical exchange and interact with the hydrophobic part of the co-aggregates. Our findings suggest a model for surfactant-induced aggregation where free peptide and surfactant initially co-aggregate to dynamic globular oligomers and eventually form elongated fibrils. When interacting with ?-structure promoting substances, such as surfactants, A? is kinetically driven toward an aggregation-prone state.

SUBMITTER: Abelein A

PROVIDER: S-EPMC5395029 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Formation of dynamic soluble surfactant-induced amyloid β peptide aggregation intermediates.

Abelein Axel A Kaspersen Jørn Døvling JD Nielsen Søren Bang SB Jensen Grethe Vestergaard GV Christiansen Gunna G Pedersen Jan Skov JS Danielsson Jens J Otzen Daniel E DE Gräslund Astrid A

The Journal of biological chemistry 20130617 32

Intermediate amyloidogenic states along the amyloid β peptide (Aβ) aggregation pathway have been shown to be linked to neurotoxicity. To shed more light on the different structures that may arise during Aβ aggregation, we here investigate surfactant-induced Aβ aggregation. This process leads to co-aggregates featuring a β-structure motif that is characteristic for mature amyloid-like structures. Surfactants induce secondary structure in Aβ in a concentration-dependent manner, from predominantly ...[more]

PMID: 23775077

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Project description:Amyloid diseases are degenerative pathologies, highly prevalent today because they are closely related to aging, that have in common the erroneous folding of intrinsically disordered proteins (IDPs) which aggregate and lead to cell death. Type 2 Diabetes involves a peptide called human islet amyloid polypeptide (hIAPP), which undergoes a conformational change, triggering the aggregation process leading to amyloid aggregates and fibers rich in β-sheets mainly found in the pancreas of all diabetic patients. Inhibiting the aggregation of amyloid proteins has emerged as a relevant therapeutic approach and we have recently developed the design of acyclic flexible hairpins based on peptidic recognition sequences of the amyloid β peptide (Aβ1-42) as a successful strategy to inhibit its aggregation involved in Alzheimer's disease. The present work reports the extension of our strategy to hIAPP aggregation inhibitors. The design, synthesis, conformational analyses, and biophysical evaluations of dynamic β-hairpin like structures built on a piperidine-pyrrolidine β-turn inducer are described. By linking to this β-turn inducer three different arms (i) pentapeptide, (ii) tripeptide, and (iii) α/aza/aza/pseudotripeptide, we demonstrate that the careful selection of the peptide-based arms from the sequence of hIAPP allowed to selectively modulate its aggregation, while the peptide character can be decreased. Biophysical assays combining, Thioflavin-T fluorescence, transmission electronic microscopy, capillary electrophoresis, and mass spectrometry showed that the designed compounds inhibit both the oligomerization and the fibrillization of hIAPP. They are also capable to decrease the aggregation process in the presence of membrane models and to strongly delay the membrane-leakage induced by hIAPP. More generally, this work provides the proof of concept that our rational design is a versatile and relevant strategy for developing efficient and selective inhibitors of aggregation of amyloidogenic proteins.

Dataset Information

Formation of dynamic soluble surfactant-induced amyloid ? peptide aggregation intermediates.

Publications

Formation of dynamic soluble surfactant-induced amyloid β peptide aggregation intermediates.

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