Alzheimer’s disease is a debilitating disorder confronting ageing populations worldwide. It is increasingly accepted that Alzheimer’s disease is brought about by an increased production of the amyloid β (Aβ) peptide, which is neurotoxic and compromises neuronal function (Selkoe, 2002
). The peptide arises through the cleavage of the amyloid precursor protein (APP; Kang et al.
) by the sequential cleavage of β-site APP-cleaving enzyme (BACE) and the protein complex γ-secretase. APP is a type I transmembrane protein with a large extracellular portion and may play a role in signalling (see, for example, Cao & Sudhof, 2001
) or interaction with the extracellular matrix (Rossjohn et al.
APP is able to bind Cu ions (Hesse et al.
) and can modulate the level of copper ions in the brain by transporting the ions in and out of neurones (White et al.
; Maynard et al.
; Bellingham et al.
). The binding of Cu2+
ions to the extracellular copper-binding domain (CuBD) can lower the production of Aβ in cultured cells (Borchardt et al.
). The beneficial effects of Cu2+
binding to the APP have been demonstrated recently in two independent transgenic mouse studies. By supplementing the drinking water with Cu2+
, the survival of APP23 mice (carrying a mutant APP that overproduces Aβ) was improved, while there was increased bioavailable Cu2+
and reduced Aβ in the brain (Bayer et al.
). Similar effects were achieved by crossing TgCRND8 mice with mice that have raised brain Cu levels owing to the expression of a mutant copper transporter CuATPase7b. This resulted in decreased amyloid plaque and plasma Aβ levels (Phinney et al.
). Structural studies of Cu2+
binding to APP will thus aid the discovery of drugs that mimic the beneficial effects of Cu2+
in and may lead to a treatment for Alzheimer’s disease.
The structure of the apo form of the CuBD has been determined using NMR spectroscopy (Barnham et al.
). The structure was found to consist of an α-helix packed against a three-strand β-sheet, a fold also observed in several copper chaperones. Copper-binding residues were inferred by titration of Cu2+
ions into a solution of CuBD. The resonance peaks of His147, His151, Tyr168 and Met170 were broadened owing to the paramagnetic interference of Cu2+
. A crystallographic study of the CuBD has been pursued to confirm these residues as ligands, to study the binding site in detail and to understand the copper-reduction mechanism.