The interaction of amyloid-β (Aβ) with endogenous metal ions is thought to play a role in the pathogenesis of Alzheimer’s disease (AD). However, limited tools exist to study and modulate Aβ-metal binding. The Meade lab has developed cobalt(III) Schiff base (Co(III)-sb) complexes as protein inhibitors that competitively displace metals from proteins. This work describes the development of Co(III)-sb as both a tool for studying metal-Aβ interactions and a therapeutic for ameliorating metal-mediated Aβ toxicity in AD. Effects of Co(III)-sb on Aβ aggregation are explored using a multimethodological approach combining ThT fluorescence, CD spectroscopy, TEM, and AFM. In addition, kinetic aggregation data are modeled using AmyloFit yielding mechanistic insight into the effects of Co(III)-sb on the microscopic processes underlying Aβ aggregation. Aggregation data on the effects of Co(III)-sb binding is further complemented with the addition of computational modeling using MD simulations. This work also explores competitive metal displacement, measurement of ROS and markers of oxidative stress, and effects of Co(III)-sb on Ab-mediated cellular toxicity. Finally, the last chapter outlines a secondary project towards the development of novel photocleavable contrast agents for TEM.

Creator

• Roberts, Kaleigh Filisa

DOI

• https://doi.org/10.21985/n2-1k0t-jr55

Subject

• Biology
• Biochemistry
• Neurosciences

Language

• en

Alternate Identifier

• etdadmin_upload_773649
• http://dissertations.umi.com/northwestern:15349

Keyword

• amyloid-beta
• aggregation
• cobalt(III) Schiff base
• coordination complex

Date created

• 2018-01-01

Resource type

• Dissertation

Rights statement

• In Copyright