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.
The misfolding and self-assembly of amyloid-β (Aβ) 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 Zn(2+) 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 Aβ fibre growth are affected at a range of Zn(2+) concentrations and we use transmission electron microscopy to characterise the aggregate assemblies formed. We demonstrate that for Aβ(1-40), and Aβ(1-42), as little as 0.01mol equivalent of Zn(2+) (100nM) is sufficient to greatly perturb the formation of amyloid fibres irreversibly. Instead, Aβ(1-40) assembles into short, rod-like structures that pack tightly together into ordered stacks, whereas Aβ(1-42) forms short, crooked assemblies that knit together to form a mesh of disordered tangles. Our data suggest that a small number of Zn(2+) ions are able to influence a great many Aβ molecules through the rapid exchange of Zn(2+) between Aβ peptides. Surprisingly, although Cu(2+) binds to Aβ 10,000 times tighter than Zn(2+), the effect of Zn(2+) on Aβ assembly dominates in Cu(2+)/Zn(2+) mixtures, suggesting that trace levels of Zn(2+) must have a profound effect on extracellular Aβ accumulation. Trace Zn(2+) levels profoundly influence Aβ assembly even at concentrations weaker than its affinity for Aβ. These observations indicate that inhibitors of fibre assembly do not necessarily have to be at high concentration and affinity to have a profound impact.
School of Biological and Biochemical Sciences, Queen Mary University of London, London, E1 4NS, UK.
Christian J
CJ
Matheou
School of Biological and Biochemical Sciences, Queen Mary University of London, London, E1 4NS, UK.
Nadine D
ND
Younan
School of Biological and Biochemical Sciences, Queen Mary University of London, London, E1 4NS, UK. Electronic address: j.viles@qmul.ac.uk.
John H
JH
Viles
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D003300:Copper / Q000378:metabolism*; D006801:Humans; D007477:Ions / Q000378:metabolism*; D007700:Kinetics; D066329:Protein Aggregates / Q000502:physiology; D017510:Protein Folding; D015032:Zinc / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D007477:Ions; D066329:Protein Aggregates; D003300:Copper; D015032:Zinc
Alzheimer's disease; Aβ; aggregation; copper; zinc