Structure-neurotoxicity relationships of amyloid β-protein oligomers

被引:653
作者
Ono, Kenjiro [1 ,2 ,3 ,4 ]
Condron, Margaret M. [1 ,2 ,3 ]
Teplow, David B. [1 ,2 ,3 ]
机构
[1] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA
[2] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA
[3] Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90095 USA
[4] Kanazawa Univ, Grad Sch Med Sci, Dept Neurol & Neurobiol & Aging, Kanazawa, Ishikawa 9208640, Japan
基金
美国国家卫生研究院;
关键词
Alzheimer's disease; toxicity; ALZHEIMERS-DISEASE; SYNAPTIC PLASTICITY; SECRETED OLIGOMERS; CROSS-LINKING; PEPTIDE; FIBRILLOGENESIS; AGGREGATION; ASSEMBLIES; TOXICITY; SCRAPIE;
D O I
10.1073/pnas.0905127106
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
beta-protein (A beta) oligomers may be the proximate neurotoxins in Alzheimer's disease (AD). "Oligomer" is an ill-defined term because many kinds have been reported and they often exist in rapid equilibrium with monomers and higher-order assemblies. We report here results of studies in which specific oligomers have been stabilized structurally, fractionated in pure form, and then studied by using a combination of CD spectroscopy, Thioflavin T fluorescence, EM, atomic force microscopy (AFM), and neurotoxicity assays. A beta monomers were largely unstructured, but oligomers exhibited order-dependent increases in beta-sheet content. EM and AFM data suggest that dimerization and subsequent monomer addition are processes in which significant and asymmetric monomer conformational changes occur. Oligomer secondary structure and order correlated directly with fibril nucleation activity. Neurotoxic activity increased disproportionately (order dependence > 1) with oligomer order. The structure-activity correlations reported here significantly extend our understanding of the conformational dynamics, structure, and relative toxicity of pure A beta oligomers of specific order.
引用
收藏
页码:14745 / 14750
页数:6
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