Coordination of redox active metal ions to the amyloid precursor protein and to amyloid-β peptides involved in Alzheimer disease. Part 1: An overview

Metal ions, mainly copper, zinc and iron, have been involved in several processes associated with the etiology of Alzheimer disease (AD). Amyloid deposits found in AD patients’ brains, known as senile plaques, are one of the morphological hallmarks of this neurodegenerative disorder. They are mostly constituted of aggregated and fibrillar forms of amyloid-β (Aβ) peptides but also contain high concentrations of metal ions (in the mM range). Because the Aβ peptide in its monomeric soluble form exist in healthy patients, step(s) in the process leading to the formation of the senile plaques is(are) key for the Aβ neurotoxicity. Aβ is obtained by specific cleavage of the Amyloid Precursor Protein (APP). Both Aβ peptides and APP contain metal ions binding sites and metal ions coordination may impact their intrinsic properties. For instance, in the case of Aβ peptides, metal ions modulate Aβ aggregation propensity and redox properties of redox active ions such as copper and iron are altered by binding to Aβ.The main objective of the present review is to give an overview of the structural evidence available nowadays concerning coordination to APP and Aβ peptides of redox active ions, i.e.   copper(I/II) and iron(II/III). Copper(II) site in the so-called copper binding site of APP was determined by X-ray crystallography and is {Nimτ(His147)Nimπ(His151),PhO−(Tyr168),2Owater}. More recently, in APP, a copper(II) site made of four imidazole rings from His outside the copper binding domain was characterized by X-ray diffraction. Two copper(II) sites in Aβ co-exist at physiological pH, noted components I and II, where I (resp.II) is predominant at lower (resp. higher) pH. In I and II, the equatorial binding sites of copper(II) are {NH2 (Asp1), CO (Asp1–Ala2), Nim (His6), Nim (His13 or His14),} and {NH2 (Asp1), N− (Asp1–Ala2), CO (Ala2–Glu3), Nim (His6 or His13 or His14)}, respectively. Copper(I) is linearly bound to Aβ via two imidazole rings from the His residues. Such highly different environments of copper in its two redox states impact the properties of the copper redox couple and will be briefly commented on in the present review. Regarding iron binding to APP and Aβ, preliminary data, which essentially show that iron(II) is the sole redox state able to interact with APP and Aβ, are described.

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► Role of metal ions in the amyloid cascade in the context of AD is described.
► Structural features of Cu(I), Cu(II) and Fe(II) binding to APP and Aβ are reviewed.
► Impact of Cu(I) and Cu(II) coordination on the redox properties of Cu(Aβ) complex is discussed.