Photoactive metal complexes for studying amyloid-β aggregates

Amyloid-β is a short peptide produced in the brain, which self-assembles into large aggregates. This process is known to be involved in the development of Alzheimer’s disease. Because of this link, there is a significant interest in developing probes that are capable of sensing and reporting on this structural conversion. Previous work in our lab by Dr. Nate Cook showed that [Ru(bpy)2(dppz)]2+ exhibits a photoluminescence light-switching response for the formation of Aβ fibrils. This thesis focuses on studying of the interaction of a rhenium dipyridophenazine complex, [Re(CO)3(dppz)(Py)]+, with Aβ aggregates. Chapter 1 is an overview of the probes that have been developed for in vitro, in vivo, and Ex vivo detection of Amyloid monomers, oligomers, and fibrils. Chapter 2 details the light-switching of [Re(CO)3(dppz)(Py)]+ in the presence of Aβ fibrils, and more importantly, explains the unique photo-induced oxidation capability of this complex, which is coupled with an unexpected light-switching enhancement (secondary light-switching effect). The application of this secondary light-switching effect is explained by utilizing it in detecting Aβ aggregation with enhanced sensitivity. Chapter 3 focuses on the characterization of the binding between the [Re(CO)3(dppz)(Py)]+ and Aβ fibrils, as well as identifying the oxidation site. Due to the fact that the oxidation is a chemical modification on the peptide, it is used as a chemical footprint of the probe binding site on the Aβ fibril. This is of significant importance as it provides empirical support for the proposed simulated binding site. Binding and Job-plot assays along with several experiments were performed to provide further empirical information about the interaction, which were shown to be consistent with the proposed binding site. Chapter 4 describes the development of a photoluminescence anisotropy method using a ruthenium always-on probe, [Ru(bpy)2(dpqp)]2+, to track the formation of toxic oligomeric species, which are challenging to detect using other techniques. Optimization were performed to find proper experimental conditions, and the probe was shown to track the formation of fibril, oligomer, and low molecular-weight aggregates in real-time. The assay was analyzed with gel electrophoresis to further support the capability of this probe. MTT assaying of N2a cell line showed that the detected species were indeed toxic.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Natural Sciences

Grantor

Rice University

Year dc:date.issued

2017

Author dc:creator

• Aliyan, Amirhossein

Advisor dc:contributor.advisor

• Martí, Angel A.

• Alzheimer's Disease
• Amyloid-β
• ruthenium
• rhenium
• Inorganic Chemistry
• Biochemistry
• Spectroscopy
• light-switching
• photoluminescence
• fluorescence
• photo-oxidation
• Mass Spectrometry
• MD simulation

Statement dc:rights

• Copyright is held by the author, unless otherwise indicated. Permission to reuse, publish, or reproduce the work beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.

Language dc:language.iso

eng

Handle dc:identifier.uri

https://hdl.handle.net/1911/105530

OAI identifier oai:identifier

oai:repository.rice.edu:1911/105530