Alzheimer’s Disease (AD) is the sixth leading cause of death in the United States and the most common cause of dementia worldwide. Yet, there are no methods to cure nor reverse the neurodegenerative disease’s effects due to the elusiveness of AD pathology. The “metal hypothesis” of Alzheimer’s Disease states that metals such as CuI/II, ZnII, and FeII/III bind to Ab peptides to form aggregates that disrupt membranes or undergo redox cycling aerobically in the presence of CuI/II or FeII/III and a reducing agent to generate reactive oxygen species (ROS). These effects also lead to neuronal cell death or weakened synaptic cell signaling. Although still controversial, depending on the experimental conditions and type of Ab species, inhibitory effects have also been observed. For example, CuII ions are known to inhibit aggregation and fibrillation by ZnII ions, while other studies have shown that ZnII plays a pivotal role in attenuating non-toxic plaque formation and is proposed to be neuroprotective. To explain these contradictory results, more controlled studies are required to uncover the important driving mechanisms by which metals play a role in Ab oligomerization and ROS production. Here we present studies using fluorescence anisotropy and UV-Vis spectroscopy to demonstrate the effects of exogenous metals on Aβ and metallated- Ab. These studies can be utilized to characterize the distinct effects and mechanisms of each metal species and identify significant therapeutic targets to promote AD drug discovery.

Distinct impact of metals ions on beta-amyloid aggregation and Alzheimer’s disease mechanisms

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