Conformation dependent monoclonal antibodies distinguish different replicating strains or conformers of prefibrillar Aβ oligomers

被引:131
作者
Kayed, Rakez [1 ,7 ]
Canto, Isabel [1 ,2 ]
Breydo, Leonid [1 ]
Rasool, Suhail [1 ]
Lukacsovich, Tamas [3 ,4 ,5 ]
Wu, Jessica [1 ]
Albay, Ricardo, III [1 ]
Pensalfini, Anna [1 ]
Yeung, Stephen [1 ]
Head, Elizabeth [6 ]
Marsh, J. Lawrence [3 ,4 ,5 ]
Glabe, Charles [1 ]
机构
[1] Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA
[2] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA
[3] Univ Calif Irvine, Dept Dev & Cell Biol, Irvine, CA 92697 USA
[4] Univ Calif Irvine, Dept Pharmacol, Irvine, CA 92697 USA
[5] Univ Calif Irvine, Ctr Dev Biol, Irvine, CA 92697 USA
[6] Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA
[7] Univ Texas Med Branch, Dept Neurol, Galveston, TX 77555 USA
来源
MOLECULAR NEURODEGENERATION | 2010年 / 5卷
关键词
ALZHEIMERS-DISEASE; AMYLOID FIBRILS; STRUCTURAL BASIS; SHEET STRUCTURE; PRION; PEPTIDE; NEURODEGENERATION; PATHOGENESIS; POLYMORPHISM; VARIANTS;
D O I
10.1186/1750-1326-5-57
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Background: Age-related neurodegenerative diseases share a number of important pathological features, such as accumulation of misfolded proteins as amyloid oligomers and fibrils. Recent evidence suggests that soluble amyloid oligomers and not the insoluble amyloid fibrils may represent the primary pathological species of protein aggregates. Results: We have produced several monoclonal antibodies that specifically recognize prefibrillar oligomers and do not recognize amyloid fibrils, monomer or natively folded proteins. Like the polyclonal antisera, the individual monoclonals recognize generic epitopes that do not depend on a specific linear amino acid sequence, but they display distinct preferences for different subsets of prefibrillar oligomers. Immunological analysis of a number of different prefibrillar A beta oligomer preparations show that structural polymorphisms exist in A beta prefibrillar oligomers that can be distinguished on the basis of their reactivity with monoclonal antibodies. Western blot analysis demonstrates that the conformers defined by the monoclonal antibodies have distinct size distributions, indicating that oligomer structure varies with size. The different conformational types of A beta prefibrillar oligomers can serve as they serve as templates for monomer addition, indicating that they seed the conversion of A beta monomer into more prefibrillar oligomers of the same type. Conclusions: These results indicate that distinct structural variants or conformers of prefibrillar A beta oligomers exist that are capable of seeding their own replication. These conformers may be analogous to different strains of prions.
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页数:10
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