Cross-Seeding Interaction between β-Amyloid and Human Islet Amyloid Polypeptide

Abstract

Alzheimer's disease (AD) and type 2 diabetes (T2D) are two common protein misfolding diseases. Increasing evidence suggests that these two diseases may be correlated with each other via cross-sequence interactions between β-amyloid peptide (Aβ) associated with AD and human islet amyloid polypeptide (hIAPP) associated with T2D. However, little is known about how these two peptides work and how they interact with each other to induce amyloidogenesis. In this work, we study the effect of cross-sequence interactions between Aβ and hIAPP peptides on hybrid amyloid structures, conformational changes, and aggregation kinetics using combined experimental and simulation approaches. Experimental results confirm that Aβ and hIAPP can interact with each other to aggregate into hybrid amyloid fibrils containing β-sheet-rich structures morphologically similar to pure Aβ and hIAPP. The cross-seeding of Aβ and hIAPP leads to the coexistence of both a retarded process at the initial nucleation stage and an accelerated process at the fibrillization stage, in conjunction with a conformational transition from random structures to α-helix to β-sheet. Further molecular dynamics simulations reveal that Aβ and hIAPP oligomers can efficiently cross-seed each other via the association of two highly similar U-shaped β-sheet structures; thus, conformational compatibility between Aβ and hIAPP aggregates appears to play a key role in determining barriers to cross-seeding. The cross-seeding effects in this work may provide new insights into the molecular mechanisms of interactions between AD and T2D.

HP-β-cyclodextrin as an inhibitor of amyloid-β aggregation and toxicity

“…As a control, for the pure Aβ 1-42 peptides incubated at 25 µΜ, ThT profile showed a typical nucleation-polymerization aggregation profiles, consisting of a very short lag phase of 1 h, a rapid growth phase between 2-7 h, and a final equilibrium phase after 7 h, where the final ThT fluorescence intensity reflects the amount of fibrillar material formed. Since pure Aβ at 25 µM experienced rapid aggregation at the early stage, lag phase only existed for a very short time period (~1 h), consistent with our previous works 12, 36,45 . In Fig.…”

“…To prevent reinventing the wheel, we proposed to search the existing drug database for other diseases to identify potential Aβ inhibitors. Since pure Aβ at 25 µM experienced rapid aggregation at the early stage, lag phase only existed for a very short time period (~1 h), consistent with our previous works 12, 36,45 . Experimental data showed that HP-β-CD were not only nontoxic to cells, but also greatly inhibited Aβ fibrillation and reduced Aβ-induced toxicity in a concentration-dependent manner.…”

Experimental and Computational Protocols for Studies of Cross-Seeding Amyloid Assemblies

“…Centrifuge the Aβ-hIAPP mixture solution at 13,148 × g for 30 min at 4 °C to remove any potential oligomers, followed by extracting 90% of the top Aβ-hIAPP solution (1.8 mL) in the monomeric state of both peptides for cross-seeding tests [23] (Fig 2). …”

Transmission des lésions amyloïdes de la maladie d’Alzheimer : apports des modèles animaux

“…In vitro, l'hété-ronucléation d'Ab par d'autres protéines amyloïdes telles que la caséine, l'a-synucléine (impliquée dans la maladie de Parkinson) ou des dépôts amyloïdes des îlots de Langerhans pancréatiques (« Islet Amyloid Protein » (IAPP, s'accumulant dans le diabète de type II)) a été montrée (O'Nuallain et al 2004;Ono et al 2014;Hu et al 2015). Les données in vivo sont plus contradictoires.…”