On the Seeding and Oligomerization of pGlu-Amyloid Peptides (in vitro)
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- 作者：Stephan Schilling ; Thomas Lauber ; Michael Schaupp ; Susanne Manhart ; Eike Scheel ; Gerald Bö ; hm ; Hans-Ulrich Demuth
- 刊名：Biochemistry
- 出版年：2006
- 出版时间：October 17, 2006
- 年：2006
- 卷：45
- 期：41
- 页码：12393 - 12399
- 全文大小：111K
- 年卷期：v.45,no.41(October 17, 2006)
- ISSN：1520-4995
文摘
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., A40or 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.
(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., A40or 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.