The Aβ42 Peptide and IAPP Physically Interact in a Yeast-Based Assay

Abstract

Numerous studies have demonstrated that people with type 2 diabetes mellitus (associated with IAPP peptide aggregation) show an increased incidence of Alzheimer’s disease (associated with Aβ aggregation), but the mechanism responsible for this correlation is presently unknown. Here, we applied a yeast-based model to study the interactions of IAPP with PrP (associated with TSEs) and with the Aβ42 peptide. We demonstrated that fluorescently tagged IAPP forms detergent-resistant aggregates in yeast cells. Using the FRET approach, we showed that IAPP and Aβ aggregates co-localize and physically interact in yeast cells. We also showed that this interaction is specific and that there is no interaction between IAPP and PrP in the yeast system. Our data confirmed a direct physical interaction between IAPP and Aβ42 aggregates in a living cell. Based on these findings, we hypothesize that this interaction may play a crucial role in seeding Aβ42 aggregation in T2DM patients, thereby promoting the development of AD.

Interaction of Proteins Involved in Neuronal Proteinopathies

“…The direct interaction of Aβ and amylin has been investigated by in vitro experiments [145][146][147][148], in vivo by the analysis in yeast [149] and Drosophila models [150], and in transgenic mice [139], as well as in silico, by mathematical modelling using amyloid conformations described for both peptides [129,130]. A sequence alignment of amylin and Aβ40 reveals 25% of sequence identity and 50% of sequence similarity (Figure 14A).…”

“…Thereby, these data assume direct interaction of these peptides resulted in aggravation of the disease-AD in case of T2DM and, probably, vice versa. The interaction between human amylin and Aβ have been also investigated in a yeast model system [149]. Using FRET, the authors have shown that Aβ42 and amylin co-localize and interact physically in yeast.…”