The Role of Glycation on the Aggregation Properties of IAPP

Abstract

Epidemiological evidence shows an increased risk for developing Alzheimer's disease in people affected by diabetes, a pathology associated with increased hyperglycemia. A potential factor that could explain this link could be the role that sugars may play in both diseases under the form of glycation. Contrary to glycosylation, glycation is an enzyme-free reaction that leads to formation of toxic advanced glycation end-products (AGEs). In diabetes, the islet amyloid polypeptide (IAPP or amylin) is found to be heavily glycated and to form toxic amyloid-like aggregates, similar to those observed for the Aβ peptides, often also heavily glycated, observed in Alzheimer patients. Here, we studied the effects of glycation on the structure and aggregation properties of IAPP with several biophysical techniques ranging from fluorescence to circular dichroism, mass spectrometry and atomic force microscopy. We demonstrate that glycation occurs exclusively on the N-terminal lysine leaving the only arginine (Arg11) unmodified. At variance with recent studies, we show that the dynamical interplay between glycation and aggregation affects the structure of the peptide, slows down the aggregation process and influences the aggregate morphology.

Probing TDP-43 condensation using an in silico designed aptamer

“…Interestingly, only 6% of the aggregates detected using Apt-1 were ThT-active, also at later time points, demonstrating the aptamer's ability to identify less mature oligomers that may be important in the disease pathology of TDP-43 and overcoming the limitations of current methods, such as the identification of oligomers of different size and structure. Other most commonly used approaches for the imaging and morphology studies of protein aggregates are transmission electron microscopy (TEM) 50 and atomic force microscopy (AFM) 51 . Both techniques provide qualitative and quantitative information at the nanometer level, but the former is limited in resolution and the latter requires long and complex sample preparation.…”

Inhibition of tau amyloid formation and disruption of its preformed fibrils by Naphthoquinone–Dopamine hybrid

“…The kinetics of PHF6 (Ac-VQIVYK-NH 2 ) aggregation upon incubation with or without various concentrations of the inhibitors, NQ, DA, or NQDA (PHF6: inhibitor = 5 : 1, 1 : 1, and 1 : 5) was monitored by thioflavin S (ThS) fluorescence assay. Prior to the assay, PHF6 was monomerized by treating it with HFIP, a commonly used method to monomerize amyloidogenic proteins including Aβ 42 in AD and amylin polypeptide associated with diabetes type 2 [39,40]. The nature of the PHF6 monomers was verified immediately thereafter (at time zero) by CD (see below).…”

Understanding the Role of Protein Glycation in the Amyloid Aggregation Process

“…Moreover, the AGE-modified IAPP, such as normal IAPP, is able to interact with synthetic membranes and also to exhibit cytotoxicity [ 124 ]. Recently, glycation of IAPP has been studied in the presence of MGO as glycating agent [ 125 ]. In this study, MGO has been shown to efficiently react only with IAPP Lys1 inducing both a slowdown of the IAPP aggregation process and changes in the aggregate morphology [ 125 ].…”

“…Recently, glycation of IAPP has been studied in the presence of MGO as glycating agent [ 125 ]. In this study, MGO has been shown to efficiently react only with IAPP Lys1 inducing both a slowdown of the IAPP aggregation process and changes in the aggregate morphology [ 125 ]. This study suggests that, although the only AGE-modified residue is Lys1 as in the CML-derived IAPP, differences in the AGEs produced and in the experimental conditions may play a key role in the dynamic effects induced by glycation on the aggregation process.…”