The Heterogeneous Nature of Cu2+Interactions with Alzheimer’s Amyloid-β Peptide

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive and memory impairment. Within the brain, senile plaques, which comprise extracellular deposits of the amyloid-β peptide (Aβ), are the most common pathological feature of AD. A high concentration of Cu²⁺ is found within these plaques, which are also areas under oxidative stress. Laboratory work has shown that in vitro Aβ will react with Cu²⁺ to induce peptide aggregation and the production of reactive oxygen species. As such, this interaction offers a possible explanation for two of the defining pathological features observed in the AD brain: the presence of amyloid plaques, which consist largely of insoluble Aβ aggregates, and the abundant oxidative stress therein. Researchers have accordingly put forth the “metals hypothesis” of AD, which postulates that compounds designed to inhibit Cu²⁺/Aβ interactions and redistribute Cu²⁺ may offer therapeutic potential for treating AD. Characterization of the pH-dependent Cu²⁺ coordination of Aβ is fundamental to understanding the neurological relevance of Cu²⁺/Aβ interactions and aiding the design of new therapeutic agents. In an effort to shed light on the problem, many experimental and theoretical techniques, using a variety of model systems, have been undertaken. The preceding decade has seen numerous conflicting spectroscopic reports concerning the nature of the Cu²⁺/Aβ coordination. As the number of studies has grown, the nature of the pH-dependent ligand environment surrounding the Cu²⁺ cation has remained a point of contention. In large part, the difficulties can be attributed to inappropriate choices of the model system or to methods that are incapable of quantitatively delineating the presence and identity of multiple Cu²⁺ coordination modes. Electron paramagnetic resonance (EPR) is the method of choice for studying paramagnetic metal–protein interactions. With the introduction of site-specific ¹⁵N, ¹⁷O, and ¹³C isotopic labels and the application of advanced techniques, EPR is capable of eliminating much of the ambiguity. Recent EPR studies have produced the most definitive picture of the pH-dependent Cu²⁺ coordination modes of Aβ and enabled researchers to address the inconsistencies present in the literature. In this Account, we begin by briefly introducing the evidence for a role of Cu²⁺ in AD as well as the potential physiological and therapeutic implications of that role. We then outline the EPR methodology used to resolve the molecular details of the Cu²⁺/Aβ interactions. No drugs are currently available for altering the course of AD, and existing therapies only offer short-term symptomatic relief. This focused picture of the role of Cu²⁺ in AD-related plaques offers welcome potential for the development of new methods to combat this devastating disease.