Oligomerization of amyloid
(A
) peptides is the decisive event in the development ofAlzheimer's disease (AD), the most common neurogenerative disorder in developed countries. Recentevidence links this conformation-driven process to primary- and secondary-structure modifications ofA
. The N and C terminus of deposited A
has been shown to possess conspicuous heterogeneity. Whilethe C-terminally longer form of A
, i.e., A
(42), is considered more amyloidogenic, the role of theN-terminal modifications, e.g., truncation and glutamate cyclization accounting for the majority of thedeposited peptides, is less understood. In the present study, we characterized the oligomerization andseeding capacity of pGlu-amyloid peptides using two unrelated techniques based on flow cytometry orflourescence dye binding. Under different conditions and irrespective of the C terminus of A
, i.e., A
40or 42, pGlu-modified peptides displayed an up to 250-fold accelerated initial formation of aggregatescompared to unmodified A
. The accelerated seed formation is accompanied by a change in theoligomerization kinetics because of N-terminal pGlu formation. Furthermore, the formation of mixedaggregates consisting of either pGlu-A
(3-42) or ADan or ABri and A
(1-42) was investigated byA
fluorescence labeling in flow cytometry. The results suggest that pGlu-modified peptides are potentialseeding species of aggregate formation
in vivo. The data presented here and the abundance of pGlu peptidesin amyloidoses, such as FBD and AD, suggest pGlu-amyloid peptides as a species with biophysicalcharacteristics that might be in particular crucial for the initiation of the disease.
