The Rapid Exchange of Zinc 2+ Enables Trace Levels to Profoundly Influence Amyloid-β Misfolding and Dominates Assembly Outcomes in Cu 2+/Zn 2+ Mixtures

JOURNAL OF MOLECULAR BIOLOGY

卷:428

Article

Matheou, Christian J.¹  Younan, Nadine D.¹  Viles, John H.¹ 

[1] Queen Mary Univ London, Sch Biol & Biochem Sci, London E1 4NS, England

关键词: Alzheimer's disease;    zinc;    copper;    A beta;    aggregation;   

DOI  :  10.1016/j.jmb.2016.05.017

来源: Elsevier

【 摘 要 】

The misfolding and self-assembly of amyloid-beta (A beta) into oligomers and fibres is fundamental to Alzheimer's disease pathology. Alzheimer's disease is a multifaceted disease. One factor that is thought to have a significant role in disease aetiology is Zn2+ homeostasis, which is disrupted in the brains of Alzheimer's disease sufferers and has been shown to modulate Alzheimer's symptoms in animal models. Here, we investigate how the kinetics of A beta fibre growth are affected at a range of Zn2+ concentrations and we use transmission electron microscopy to characterise the aggregate assemblies formed. We demonstrate that for A beta((1-40)), and A beta((1-42)), as little as 0.01 mol equivalent of Zn2+ (100 nM) is sufficient to greatly perturb the formation of amyloid fibres irreversibly. Instead, A beta((1-40)) assembles into short, rod-like structures that pack tightly together into ordered stacks, whereas A beta((1-42)) forms short, crooked assemblies that knit together to form a mesh of disordered tangles. Our data suggest that a small number of Zn2+ ions are able to influence a great many A beta molecules through the rapid exchange of Zn2+ between A beta peptides. Surprisingly, although Cu2+ binds to A beta 10,000 times tighter than Zn2+, the effect of Zn2+ on A beta assembly dominates in Cu2+/Zn2+ mixtures, suggesting that trace levels of Zn2+ must have a profound effect on extracellular A beta accumulation. Trace Zn2+ levels profoundly influence A beta assembly even at concentrations weaker than its affinity for A beta. These observations indicate that inhibitors of fibre assembly do not necessarily have to be at high concentration and affinity to have a profound impact. (C) 2016 Published by Elsevier Ltd.

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