The Amyloid-β Peptide of Alzheimer’s Disease Binds CuI in a Linear Bis-His Coordination Environment: Insight into a Possible Neuroprotective Mechanism for the Amyloid-β Peptide

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Abstract
Oxidative stress has been suggested to contribute to neuronal apoptosis associated with Alzheimer’s disease (AD). Copper may participate in oxidative stress through redox-cycling between its +2 and +1 oxidation states to generate reactive oxygen species (ROS). In vitro, copper binds to the amyloid-β peptide of AD, and in vivo, copper is associated with amyloid plaques characteristic of AD. As a result, the AβCuI complex may be a critical reactant involved in ROS associated with AD etiology. To characterize the AβCuI complex, we have pursued X-ray absorption (XAS) and electron paramagnetic resonance (EPR) spectroscopy of AβCuII and AβCuI (produced by ascorbate reduction of AβCuII). The AβCuII complex Cu K-edge XAS spectrum is indicative of a square-planar CuII center with mixed N/O ligation. Multiple scattering analysis of the extended X-ray absorption fine structure (EXAFS) data for AβCuII indicates that two of the ligands are imidazole groups of histidine ligands, indicating a (NIm)2(N/O)2 CuII ligation sphere for AβCuII. After reduction of the AβCuII complex with ascorbate, the edge region decreases in energy by ∼4 eV. The X-ray absorption near-edge spectrum region of AβCuI displays an intense pre-edge feature at 8984.1(2) eV. EXAFS data fitting yielded a two-coordinate geometry, with two imidazole ligands coordinated to CuI at 1.877(2) Å in a linear geometry. Ascorbate reduction of AβCuII under inert atmosphere and subsequent air oxidation of AβCuI to regenerate AβCuII was monitored by low-temperature EPR spectroscopy. Slow reappearance of the AβCuII EPR signal indicates that O2 oxidation of the AβCuI complex is kinetically sluggish and Aβ damage is occurring following reoxidation of AβCuI by O2. Together, these results lead us to hypothesize that CuI is ligated by His13 and His14 in a linear coordination environment in Αβ, that Aβ may be playing a neuroprotective role, and that metal-mediated oxidative damage of Aβ occurs over multiple redox cycles.