On the seeding and oligomerization of pGlu-amyloid peptides (in vitro).
Oligomerization of amyloid beta (Abeta) peptides is the decisive event in the development of Alzheimer's disease (AD), the most common neurogenerative disorder in developed countries. Recent evidence links this conformation-driven process to primary- and secondary-structure modifications of Abeta. The N and C terminus of deposited Abeta has been shown to possess conspicuous heterogeneity. While the C-terminally longer form of Abeta, i.e., Abeta (42), is considered more amyloidogenic, the role of the N-terminal modifications, e.g., truncation and glutamate cyclization accounting for the majority of the deposited peptides, is less understood. In the present study, we characterized the oligomerization and seeding capacity of pGlu-amyloid peptides using two unrelated techniques based on flow cytometry or flourescence dye binding. Under different conditions and irrespective of the C terminus of Abeta, i.e., Abeta40 or 42, pGlu-modified peptides displayed an up to 250-fold accelerated initial formation of aggregates compared to unmodified Abeta. The accelerated seed formation is accompanied by a change in the oligomerization kinetics because of N-terminal pGlu formation. Furthermore, the formation of mixed aggregates consisting of either pGlu-Abeta (3-42) or ADan or ABri and Abeta (1-42) was investigated by Abeta fluorescence labeling in flow cytometry. The results suggest that pGlu-modified peptides are potential seeding species of aggregate formation in vivo. The data presented here and the abundance of pGlu peptides in amyloidoses, such as FBD and AD, suggest pGlu-amyloid peptides as a species with biophysical characteristics that might be in particular crucial for the initiation of the disease.
Schilling
Stephan
S
Probiodrug AG, Halle/Saale, Germany.
Lauber
Thomas
T
Schaupp
Michael
M
Manhart
Susanne
S
Scheel
Eike
E
Böhm
Gerald
G
Demuth
Hans-Ulrich
HU
D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D052160:Benzothiazoles; D005434:Flow Cytometry; D005456:Fluorescent Dyes; D006801:Humans; D066298:In Vitro Techniques; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry; D020836:Protein Structure, Quaternary; D011761:Pyrrolidonecarboxylic Acid / Q000737:chemistry; D013844:Thiazoles
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D005456:Fluorescent Dyes; D010446:Peptide Fragments; D013844:Thiazoles; C009462:thioflavin T; D011761:Pyrrolidonecarboxylic Acid