UC San Diego

Although the pathological aggregation and deposition of A[beta]-amyloid (A[beta]) peptides in the brain has long been implicated as the key event leading to the onset of Alzheimer's disease (AD), there is still no disease- modifying therapeutic or definitive diagnostic method to diagnose, monitor, or treat AD. Compelling evidence has shown a strong correlation between accumulation of neurotoxic A[beta] peptides and oxidative damage in the brains of AD sufferers. One hypothesis for this correlation involves the direct and harmful interaction of aggregated A[beta] peptides with enzymes responsible for maintaining normal levels of reactive oxygen species. Identification of specific, destructive interactions of A[beta] peptides with cellular anti-oxidant enzymes would represent an important step towards understanding the pathogenicity of A[beta] peptides in AD and designing an effective strategy to manage this disease. Therefore, the focus of this dissertation is to : 1) identify direct and harmful binding interactions between aggregated A[beta] peptides and anti-oxidant enzymes that contribute to the pathogenesis of AD, 2) inhibit these destructive interactions using A[beta]-binding small molecules capable of generating protein-resistive surface coatings on aggregated A[beta] peptides, and 3) develop a general strategy to deliver diagnostic and therapeutic agents across the restrictive blood-brain barrier (BBB). In this dissertation, small molecules capable of generating protein-resistive surface coatings on aggregated A[beta] peptides were used to probe the interaction of Aβ with cellular anti-oxidant enzymes. This dissertation supports the important role of intracellular catalase- amyloid interactions in A[beta]-induced oxidative stress and proposes a novel molecular strategy of generating protein-resistive surface coatings on aggregated A[beta] peptides to inhibit such harmful interactions in AD. The development of high payload brain-targeting magnetic nanoparticles that have the ability to act as a diagnostic imaging agent while simultaneously providing a multivalent scaffold for conjugation of drugs and brain-targeting vectors was also explored. This dissertation provides evidence that magnetic nanoparticles conjugated to transferrin enhances the transport of nanoparticles across the BBB by receptor-mediated transcytosis. Collectively, these findings provide new information on the interaction of aggregated A[beta] peptides with cellular components that contribute to AD, propose a strategy to inhibit these interactions, and suggest that receptor-mediated transcytosis may be a promising route for the delivery of molecules across the BBB