Metal ions and amyloid fiber formation in neurodegenerative diseases. Copper, zinc and iron in Alzheimer's, Parkinson's and prion diseases

There are a group of diseases associated with protein misfolding and accumulation into amyloid fibers. Many of these diseases have a major impact on human health, in particular, Alzheimer's (AD), Parkinson's (PD) and prion diseases. The focus of this review is to highlight how metal ions influence amyloid formation in a number of neurodegenerative diseases. Firstly, the various mechanisms by which metal ions might influence the kinetics of amyloid fiber formation are surveyed. The coordination of metal ions to a number of amyloidogenic proteins, with an emphasis on metal binding to intact fibers is reviewed. The kinetics of amyloid formation and the influence Cu2+, Zn2+, Fe3+ and Ca2+ have on amyloid-beta peptide (Aβ) fiber formation in AD is described in detail. The effect of metal ions on fibril formation for other amyloidogenic proteins, in particular Cu2+ binding to α-synuclein (αSyn) and the prion protein (PrP), are also reviewed. The mechanism by which metal ions might influence neurotoxicity of amyloids is also discussed. Levels of metal ions found at the synapse are described and related to the affinity of metal ions for Aβ, PrP and αSyn. In vivo evidence for a link between metal ions in these common neurodegenerative diseases, and the interplay between Aβ the prion protein and copper are reported. Finally, the possibility of a shared mechanism by which metal ions might influence amyloidosis is discussed.

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► Metal ions influence amyloid formation in a number of neurodegenerative diseases.
► Cu2+ accelerates amyloid-beta peptide fiber formation and enhances cytotoxicity.
► Mechanisms by which metal ions accelerate the kinetics of fiber formation are discussed.
► Metal ions at the synapse, and the interplay between Aβ, the prion protein and copper are discussed.