Copper Abolishes the β-Sheet Secondary Structure of Preformed Amyloid Fibrils of Amyloid-β42

被引:43
作者
House, Emily [1 ]
Mold, Matthew [1 ]
Collingwood, Joanna [2 ]
Baldwin, Alex
Goodwin, Steven
Exley, Christopher [1 ]
机构
[1] Univ Keele, Birchall Ctr, Lennard Jones Labs, Keele ST5 5BG, Staffs, England
[2] Univ Warwick, Sch Engn, Coventry CV4 7AL, W Midlands, England
基金
英国工程与自然科学研究理事会; 美国国家卫生研究院;
关键词
Aluminum; Alzheimer's disease; amyloid; A beta(42); beta-sheet; Congo red; copper; spherulites; TEM; thioflavin T; SENILE PLAQUE CORES; ALZHEIMERS-DISEASE; IN-VITRO; A-BETA; AGGREGATION; A-BETA(42); IRON; ALUMINUM; BINDING; PROTEIN;
D O I
10.3233/JAD-2009-1235
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The observation of the co-deposition of metals and amyloid-beta(42) (A beta(42)) in brain tissue in Alzheimer's disease prompted myriad investigations into the role played by metals in the precipitation of this peptide. Copper is bound by monomeric A beta(42) and upon precipitation of the copper-peptide complex thereby prevents A beta(42) from adopting a beta-sheet secondary structure. Copper is also bound by beta-sheet conformers of A beta(42), and herein we have investigated how this interaction affects the conformation of the precipitated peptide. Copper significantly reduced the thioflavin T fluorescence of aged, fibrillar A beta(42) with, for example, a 20-fold excess of the metal resulting in a ca 90% reduction in thioflavin T fluorescence. Transmission electron microscopy showed that copper significantly reduced the quantities of amyloid fibrils while Congo red staining and polarized light demonstrated a copper-induced abolition of apple-green birefringence. Microscopy under cross-polarized light also revealed the first observation of spherulites of A beta(42). The size and appearance of these amyloid structures were found to be very similar to spherulites identified in Alzheimer's disease tissue. The combined results of these complementary methods strongly suggested that copper abolished the beta-sheet secondary structure of pre-formed, aged amyloid fibrils of A beta(42). Copper may protect against the presence of beta-sheets of A beta(42) in vivo, and its binding by fibrillar A beta(42) could have implications for Alzheimer's disease therapy.
引用
收藏
页码:811 / 817
页数:7
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