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

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 A beta Cu-I complex may be a critical reactant involved in ROS associated with AD etiology. To characterize the A beta u(I) complex, we have pursued X-ray absorption (XAS) and electron paramagnetic resonance (EPR) spectroscopy of A beta Cu-II and A beta Cu-I (produced by ascorbate reduction of A beta Cu-II). The A beta Cu-II complex Cu K-edge XAS spectrum is indicative of a square-planar Cull center with mixed N/O ligation. Multiple scattering analysis of the extended X-ray absorption fine structure (EXAFS) data for A beta Cu-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 A beta Cu-II. After reduction of the A beta Cu-II complex with ascorbate, the edge region decreases in energy by similar to 4 eV. The X-ray absorption near-edge spectrum region of A beta Cu-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) angstrom in a linear geometry. Ascorbate reduction of A beta Cu-II under inert atmosphere and subsequent air oxidation of A beta Cu-I to regenerate A beta Cu-II was monitored by low-temperature EPR spectroscopy. Slow reappearance of the A beta Cu-II EPR signal indicates that O-2 oxidation of the A beta Cu-I complex is kinetically sluggish and A beta damage is occurring following reoxidation of A beta Cu-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 A beta, that A beta may be playing a neuroprotective role, and that metal-mediated oxidative damage of A beta occurs over multiple redox cycles.