Studies on the cross‐interaction between hIAPP and Aβ_25–35 and the aggregation process in binary mixture by electrospray ionization‐ion mobility‐mass spectrometry

Abstract

A wealth of epidemiological evidence indicates a strong link between type 2 diabetes (T2D) and Alzheimer's disease (AD). The fiber deposition with cross-β-sheet structure formed by self-aggregation and misfolding of amyloidogenic peptides is a common hallmark of both diseases. For the patients with T2D, the fibrils are mainly found in the islets of Langerhans that results from the accumulation of human islet amyloid polypeptide (hIAPP). The major component of aggregates located in the brain of AD patients is amyloid-β (Aβ). Many biophysical and physiological properties are shared by hIAPP and Aβ, and both peptides show similar cytotoxic mechanisms. Therefore, it is meaningful to investigate the possible cross-interactions of hIAPP and Aβ in both diseases. In this article, the segment 25-35 of Aβ was selected because Aβ 25-35 was a core region in the process of amyloid formation and showed similar aggregation tendency and toxicity with full-length Aβ. The electrospray ionization-ion mobilitymass spectrometry analysis and thioflavin T fluorescence kinetic analysis combined with transmission electron microscopy were used to explore the effects of the coexistence of Aβ 25-35 and hIAPP on the self-aggregation of both peptides and whether there was co-assembly in fibrillation. The results indicated that the aggregation of hIAPP and Aβ 25-35 had two nucleation stages in the binary mixtures. hIAPP and Aβ 25-35 had a high binding affinity and a series of hetero-oligomers formed in the mixtures of hIAPP and Aβ 25-35 in the early stage. The cross-reaction between hIAPP monomers and Aβ 25-35 monomers as well as a little of oligomers during primary nucleation stage could accelerate the aggregation of Aβ 25-35. However, owing to the obvious difference in aggregation ability between hIAPP and Aβ 25-35 , this crossinteraction had no significant impact on the self-assembly of hIAPP. Our study may offer a better understanding for exploring the molecular mechanism of the association between AD and T2D observed in clinical and epidemiological studies and developing therapeutic strategies against amyloid diseases.