Amyloid-(1-42) Rapidly Forms Protofibrils and Oligomers by Distinct Pathways in Low Concentrations of Sodium Dodecylsulfate

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• 作者：Vijayaraghavan Rangachari ; Brenda D. Moore ; Dana Kim Reed ; Leilani K. Sonoda ; Alexander W. Bridges ; Erin Conboy ; David Hartigan ; Terrone L. Rosenberry
• 刊名：Biochemistry
• 出版年：2007
• 出版时间：October 30, 2007
• 年：2007
• 卷：46
• 期：43
• 页码：12451 - 12462
• 全文大小：451K
• 年卷期：v.46,no.43(October 30, 2007)
• ISSN：1520-4995

文摘

Alzheimer's disease (AD) is characterized by large numbers of senile plaques in the brainthat consist of fibrillar aggregates of 40- and 42-residue amyloid- (A) peptides. However, the degreeof dementia in AD correlates better with the concentration of soluble A species assayed biochemicallythan with histologically determined plaque counts, and several investigators now propose that solubleaggregates of A are the neurotoxic agents that cause memory deficits and neuronal loss. These endogenousaggregates are minor components in brain extracts from AD patients and transgenic mice that expresshuman A, but several species have been detected by gel electrophoresis in sodium dodecylsulfate (SDS)and isolated by size exclusion chromatography (SEC). Endogenous A aggregation is stimulated at cellularinterfaces rich in lipid rafts, and anionic micelles that promote A aggregation in vitro may be goodmodels of these interfaces. We previously found that micelles formed in dilute SDS (2 mM) promoteA(1-40) fiber formation by supporting peptide interaction on the surface of a single micelle complex.In contrast, here we report that monomeric A(1-42) undergoes an immediate conversion to a predominant-structured conformation in 2 mM SDS which does not proceed to amyloid fibrils. The conformationalchange is instead rapidly followed by the near quantitative conversion of the 4 kDa monomer SDS gelband to 8-14 kDa bands consistent with dimers through tetramers. Removal of SDS by dialysis gave ashift in the predominant SDS gel bands to 30-60 kDa. While these oligomers resemble the endogenousaggregates, they are less stable. In particular, they do not elute as discrete species on SEC, and they arecompleted disaggregated by boiling in 1% SDS. It appears that endogenous oligomeric A aggregates arestabilized by undefined processes that have not yet been incorporated into in vitro A aggregationprocedures.