N‐terminal truncated pyroglutamyl β amyloid peptide Aβpy3‐42 shows a faster aggregation kinetics than the full‐length Aβ1‐42

Abstract

We tested directly the differences in the aggregation kinetics of three important beta amyloid peptides, the full-length Abeta1-42, and the two N-terminal truncated and pyroglutamil modified Abetapy3-42 and Abetapy11-42 found in different relative concentrations in the brains in normal aging and in Alzheimer disease. By following the circular dichroism signal and the ThT fluorescence of the solution in phosphate buffer, we found substantially faster aggregation kinetics for Abetapy3-42. This behavior is due to the particular sequence of this peptide, which is also responsible for the specific oligomeric aggregation states, found by TEM, during the fibrillization process, which are very different from those of Abeta1-42, more prone to fibril formation. In addition, Abetapy3-42 is found here to have an inhibitory effect on Abeta1-42 fibrillogenesis, coherently with its known greater infective power. This is an indication of the important role of this peptide in the aggregation process of beta-peptides in Alzheimer disease.

Structure and Toxicity of the Prefibrillar Aggregation States of Beta Peptides in Alzheimer’s Disease

“…Recently, it was demonstrated that, in similar initial buffer conditions and using three different techniques (flow cytometry, ThT fluorescence and circular dichroism), these N-terminal modified peptides aggregate much faster than the fulllength Aβ (D'Arrigo et al, 2009;Shilling et al, 2006). Altogether, the aggregation kinetics of Apy3-42 was found 20-250 by cytometry and ThT fluorescence (Shilling et al, 2006) and more than 30 times by CD (D'Arrigo et al, 2009) faster than that of A1-42 respectively, depending upon the assay method.…”

“…Altogether, the aggregation kinetics of Apy3-42 was found 20-250 by cytometry and ThT fluorescence (Shilling et al, 2006) and more than 30 times by CD (D'Arrigo et al, 2009) faster than that of A1-42 respectively, depending upon the assay method. The oligomers that form β-structure rapidly are found to be more toxic (D'Arrigo et al, 2009;Mastrangelo et al, 2006;Shilling et al, 2006). In addition the aggregation pathway of the two A leads to more toxic dynamic oligomeric states for Apy3-42 and to fibril formation for A1-42, see for instance (D'Arrigo et al, 2009) and (He & Barrow, 1999), while when the two are mixed (e.g.…”

“…The oligomers that form β-structure rapidly are found to be more toxic (D'Arrigo et al, 2009;Mastrangelo et al, 2006;Shilling et al, 2006). In addition the aggregation pathway of the two A leads to more toxic dynamic oligomeric states for Apy3-42 and to fibril formation for A1-42, see for instance (D'Arrigo et al, 2009) and (He & Barrow, 1999), while when the two are mixed (e.g. in a 1:1 ratio) Apy3-42 has an inhibitory effect on the fibrillogenesis of A1-42, favouring prefibrillar aggregation states, that are more toxic for the cells (see Figure 6) (D'Arrigo et al, 2009).…”

“…Recently, the faster aggregation kinetics after incubation time of the N-terminal and pyromodified peptides relative to the full length Aβ, were demonstrated together with significant morthological differences in the pure or mixed aggregation states (D'Arrigo et al, 2009;Shilling et al, 2006). Demuth and coll.…”

Investigating Amyloid β toxicity in Drosophila melanogaste

“…To complicate the understanding further, research has shown N-terminally modified Aβ peptides, with the most prominent forms identified starting at amino acid 3 or 11 and possessing Nterminal pyroglutamic acid (pyroE), generated from glutamic acid by the enzyme glutaminyl cyclase [109], [110]. In vitro studies have shown that small N-terminal deletions accelerate Aβ aggregation into neurotoxic fibrils compared to Aβ 1-42 [111], [112]. In the case of pyroglutamylation, the increased propensity to aggregate might be due to the higher hydrophobicity of the peptide when losing one or two charges [113] and limited N-terminal degradation [109].…”