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

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-beta peptide of AD, and in vivo, copper is associated with amyloid plaques characteristic of AD. As a result, the AbetaCu(I) complex may be a critical reactant involved in ROS associated with AD etiology. To characterize the AbetaCu(I) complex, we have pursued X-ray absorption (XAS) and electron paramagnetic resonance (EPR) spectroscopy of AbetaCu(II) and AbetaCu(I) (produced by ascorbate reduction of AbetaCu(II)). The AbetaCu(II) complex Cu K-edge XAS spectrum is indicative of a square-planar Cu(II) center with mixed N/O ligation. Multiple scattering analysis of the extended X-ray absorption fine structure (EXAFS) data for AbetaCu(II) indicates that two of the ligands are imidazole groups of histidine ligands, indicating a (N(Im))(2)(N/O)(2) Cu(II) ligation sphere for AbetaCu(II). After reduction of the AbetaCu(II) complex with ascorbate, the edge region decreases in energy by approximately 4 eV. The X-ray absorption near-edge spectrum region of AbetaCu(I) 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 Cu(I) at 1.877(2) A in a linear geometry. Ascorbate reduction of AbetaCu(II) under inert atmosphere and subsequent air oxidation of AbetaCu(I) to regenerate AbetaCu(II) was monitored by low-temperature EPR spectroscopy. Slow reappearance of the AbetaCu(II) EPR signal indicates that O(2) oxidation of the AbetaCu(I) complex is kinetically sluggish and Abeta damage is occurring following reoxidation of AbetaCu(I) by O(2). Together, these results lead us to hypothesize that Cu(I) is ligated by His13 and His14 in a linear coordination environment in Alphabeta, that Abeta may be playing a neuroprotective role, and that metal-mediated oxidative damage of Abeta occurs over multiple redox cycles.