Alzheimer’s Disease (AD) is the sixth leading cause of death in the United States with no known methods to cure, reverse or halt disease progression. The “metal hypothesis” states that FeII, CuII, ZnII, and AlII bind to truncated Aβ peptides and form soluble oligomers which deposit as senile plaques. These plaques play a crucial role in AD pathogenesis. For example, metallated-Aβ aggregates are hypothesized to disrupt membranes or generate a reactive oxygen species (ROS) through redox cycling in the presence of CuI/II or FeIII/II and a reducing agent. ROS can lead to weakened synaptic signaling and neuronal cell death. In addition, the ratio of the metal:Aβ can form a variety of metallated-Aβ species that are both soluble and neurotoxic. Neurotoxicity can depend on the size of the metallated-Aβ species as well as the type of metal present. For example, some studies suggest that CuII ions inhibit aggregation and fibrillation reactions induced by ZnII ions and may, therefore, be neuroprotective in this scenario. Regardless of the contradictory roles of metals, the most convincing piece of evidence supporting a link between metal homeostasis and the two pathological processes (Aβ1-42 aggregation and oxidative damage) comes from chelation studies showing that solubilization and removal of Aβ deposits lead to clinical improvement in patients with the AD. Studies suggest control of metal imbalances as well as Aβ concentrations are important “disease-modifying strategies”. Here we will present studies utilizing well-known metal ion capture agents, metallodithiolates or NiN2S2 ligands, as chelators to reverse Aβ aggregation. Fluorescence anisotropy, UV-Vis spectroscopy, and atomic force microscopy studies will show that interactions of Aβ with metal ions are reversible with metallodithiolate ligands. These studies will show that metallodithiolates might be a new class of ligands for reversing metal-induced Aβ aggregation as a potential disease-modifying strategy.

Metallodithiolate ligands for reversing metal ion induced aggregation of beta amyloid

255th National Meeting (2018)

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