Abstract:
:Spontaneous conversion of beta-amyloid peptide (Abeta) from soluble monomer to insoluble fibril may underlie the neurodegeneration associated with Alzheimer's disease. A complete description of Abeta self-association kinetics requires identification of the oligomeric species present and the pathway of association, as well as quantitation of rate constants and reaction order. Abeta was rendered monomeric and denatured by dissolution in 8 M urea, pH 10. "Refolding" and fibrillization were initiated by rapid dilution into phosphate-buffered saline, pH 7.4. The kinetics of growth were followed at three different concentrations, using size exclusion chromatography, dynamic light scattering, and static light scattering. A multi-step pathway for fibril formation and growth was postulated. This pathway included 1) rapid commitment to either stable monomer/dimer or unstable intermediate, 2) cooperative association of intermediate into a multimeric "nucleus," 3) elongation of the "nucleus" into filaments via addition of intermediate, 4) lateral aggregation of filaments into fibrils, and 5) fibril elongation via end-to-end association. Differential and algebraic equations describing this kinetic pathway were derived, and model parameters were determined by fitting the data. The utility of the model for identifying toxic Abeta oligomeric specie(s) is demonstrated. The model should prove useful for designing compounds that inhibit Abeta aggregation and/or toxicity.
journal_name
Biophys Jjournal_title
Biophysical journalauthors
Pallitto MM,Murphy RMdoi
10.1016/S0006-3495(01)75831-6subject
Has Abstractpub_date
2001-09-01 00:00:00pages
1805-22issue
3eissn
0006-3495issn
1542-0086pii
S0006-3495(01)75831-6journal_volume
81pub_type
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journal_title:Biophysical journal
pub_type: 杂志文章
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journal_title:Biophysical journal
pub_type: 杂志文章
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更新日期:1993-01-01 00:00:00
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journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/s0006-3495(01)75726-8
更新日期:2001-08-01 00:00:00
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pub_type: 杂志文章
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pub_type: 杂志文章
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更新日期:1985-12-01 00:00:00
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pub_type: 杂志文章
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pub_type: 杂志文章
doi:10.1016/j.bpj.2013.04.033
更新日期:2013-06-04 00:00:00
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pub_type: 杂志文章
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pub_type: 杂志文章
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更新日期:2009-06-03 00:00:00
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pub_type: 杂志文章
doi:10.1016/S0006-3495(01)75821-3
更新日期:2001-09-01 00:00:00
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pub_type: 杂志文章
doi:10.1016/j.bpj.2008.12.3954
更新日期:2009-04-22 00:00:00
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journal_title:Biophysical journal
pub_type: 杂志文章
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更新日期:2016-04-12 00:00:00
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journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/S0006-3495(00)76549-0
更新日期:2000-12-01 00:00:00
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journal_title:Biophysical journal
pub_type: 杂志文章
doi:10.1016/S0006-3495(01)76052-3
更新日期:2001-02-01 00:00:00
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pub_type: 杂志文章
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更新日期:2007-06-15 00:00:00
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pub_type: 杂志文章
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journal_title:Biophysical journal
pub_type: 杂志文章
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更新日期:2008-12-01 00:00:00
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pub_type: 杂志文章
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更新日期:1961-09-01 00:00:00
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pub_type: 杂志文章
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更新日期:1998-05-01 00:00:00
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journal_title:Biophysical journal
pub_type: 杂志文章
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更新日期:2000-06-01 00:00:00
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pub_type: 杂志文章
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更新日期:2000-01-01 00:00:00
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pub_type: 杂志文章
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更新日期:2000-04-01 00:00:00
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journal_title:Biophysical journal
pub_type: 杂志文章
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更新日期:2007-12-15 00:00:00