The cognitive decline in Alzheimer's disease (AD) resulting from neuronal cell death has no cure, identified cause, or early diagnoses.  With patient care estimated at >$604 billion/year globally, there is strong motivation to develop early diagnostics and therapeutics.  According to the �metal hypothesis of AD�, metals such as FeII, CuII, ZnII, and AlIII bind to beta amyloid (A�) peptides to form oligomers and aggregates that deposit in the form of senile plaques.   These metallated-A� species disrupt membranes or undergo redox cycling aerobically in the presence of CuI/II or FeIII/II and a reducing agent to generate reactive oxygen species (ROS).  The resulting oxidative stress leads to weakened synaptic cell signaling and neuronal cell death.  However, depending on the experimental conditions and type of beta amyloid aggregate; inhibitory effects have been observed.  For example, CuII ions are known to inhibit aggregation and fibrillation by ZnII ions.  Consequently, a better understanding of how metals induce aggregation is crucial.  Despite these contradictory studies, the most convincing evidence that suggest there is a link between metal ions and A� comes from chelation studies showing clinical improvement of patients with AD.  These studies demonstrate that metal chelation is a sound disease modifying strategy.  While chelators are effective in vitro, there are associated toxicities in vivo, >98% fail to cross the blood brain barrier (BBB), and very few target metallated-A�.  Site-directed metal specific chelators that cross the BBB is of significant interest.  Therefore, we will present a new class of chelators with a modified architecture to target metallated-A�.  These chelators templated on gold nanoparticles that can be used as a vehicular platform to improve delivery across the BBB and metal capture.  Fluorescence anisotropy, dynamic light scattering, and the localized surface plasmon resonance band of gold nanoparticles will demonstrate the utility of these nanochelators to reverse metal-induced aggregation.

Site-directed nanochelators for reversing metal-induced protein aggregation

247th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.