Although the pathological aggregation and deposition of Aβ-amyloid (Aβ) 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 Aβ peptides and oxidative damage in the brains of AD sufferers. One hypothesis for this correlation involves the direct and harmful interaction of aggregated Aβ peptides with enzymes responsible for maintaining normal levels of reactive oxygen species. Identification of specific, destructive interactions of Aβ peptides with cellular anti-oxidant enzymes would represent an important step towards understanding the pathogenicity of Aβ 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 Aβ peptides and anti-oxidant enzymes that contribute to the pathogenesis of AD, 2) inhibit these destructive interactions using Aβ-binding small molecules capable of generating protein-resistive surface coatings on aggregated Aβ 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 Aβ 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 Aβ-induced oxidative stress and proposes a novel molecular strategy of generating protein-resistive surface coatings on aggregated Aβ 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 Aβ 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.
|Advisor:||Yang, Jerry, Chien, Shu|
|Commitee:||Heller, Michael, Koo, Edward, Sailor, Michael|
|School:||University of California, San Diego|
|School Location:||United States -- California|
|Source:||DAI-B 73/03, Dissertation Abstracts International|
|Subjects:||Neurosciences, Biochemistry, Biomedical engineering|
|Keywords:||Alzheimer's disease, Amyloid, Blood-brain barrier, Catalase, Nanoparticles, Oxidative stress, Protein-amyloid interactions|
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