Central to Alzheimer's disease is the misfolding of amyloid-beta (Aβ) peptide, which generates an assorted population of amorphous aggregates, oligomers and fibres. Metal ion homoeostasis is disrupted in the brains of sufferers of Alzheimer's disease and causes heightened Alzheimer's disease phenotype in animal models. In the present study, we demonstrate that substochiometric Cu²⁺ affects the misfolding pathway of Aβ₁₋₄₀, and the more toxic Aβ₁₋₄₂, in markedly different ways. Cu²⁺ accelerates Aβ₁₋₄₀ fibre formation. In contrast, for Aβ₁₋₄₂, substoichiometric levels of Cu²⁺ almost exclusively promote the formation of oligomeric and protofibrillar assemblies. Indeed, mature Aβ₁₋₄₂ fibres are disassembled into oligomers when Cu²⁺ is added. These Cu²⁺ stabilized oligomers of Aβ₁₋₄₂ interact with the lipid bilayer, disrupting the membrane and increasing permeability. Our investigation of Aβ₁₋₄₀/Aβ₁₋₄₂ mixtures with Cu²⁺ revealed that Aβ₁₋₄₀ neither contributed to nor perturbed formation of Aβ₁₋₄₂ oligomers, although Cu²⁺-Aβ₁₋₄₂ does frustrate Cu²⁺-Aβ₁₋₄₀ fibre growth. Small amounts of Cu²⁺ accentuate differences in the propensity of Aβ₁₋₄₀ and Aβ₁₋₄₂ to form synaptotoxic oligomers, providing an explanation for the connection between disrupted Cu²⁺ homoeostasis and elevated Aβ₁₋₄₂ neurotoxicity in Alzheimer's disease.

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.

No abstract

No abstract