Investigation of functionalized (2-Phenylpyridine)Pt(II) complexes for monitoring and interfering with amyloid aggregation

It is estimated that nearly 6 million Americans have Alzheimer’s Disease (AD), representing almost 2% of the total U.S. population. In the next 30 years this figure is expected to more than double, making Alzheimer’s one of the most pressing public health issues of our time. The issue is compounded by a lack of understanding of the root cause of AD, the obvious absence of a cure, and the lack of any long-term effective treatment regimen capable of slowing or mitigating the effects of AD.

A characteristic feature of AD is the appearance of senile plaques in brain tissue. Senile plaques are composed of amyloid fibrils –; a non-specific term used to describe insoluble fibrillar assemblies of disordered proteins. In the case of AD, the amyloid protein involved is called A-beta and, for reasons that remain obscure, A-beta accumulates in the brains of AD patients to initially form small soluble oligomers that eventually grow into long insoluble fibrils. Thus, there is an urgent need to develop methods for detecting, monitoring, and influencing the course of harmful protein aggregation. The research described in this thesis explored development of chemical labeling agents for disease-related biomarkers, specifically for AD-related amyloid assemblies. Amyloid oligomers and fibrils derived from hen egg-white lysozyme were used as a cost-effective model for A-beta fibrils important in AD, and several probes displaying “turn-on” luminescence response in the presence of amyloid fibrils were successfully constructed. One probe molecule also showed the ability to alter the form and structure of amyloid fibrils upon longer incubation. This research contributes to efforts that may ultimately lead to the discovery of new diagnostic and therapeutic approaches for amyloidogenic diseases.