Reporters of Amyloid Structural Polymorphism

Pathology due to the accumulation of misfolded protein is characteristic of many chronic neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, and multiple tauopathies. The clinical use of radioimaging ligands for early detection of Aβ pathology of Alzheimer's disease in living subjects is making it possible to identify individuals at risk before the onset of cognitive symptoms. High selectivity of the ligand for a specific protein is critical for distinguishing between diseases. There is increasing recognition that multiple polymorphic assemblies, both soluble and fibrillar, of each precursor protein exist in animal models and human subjects and, in addition, that different forms of that protein are not equally relevant to disease processes. This inability to discriminate among such forms affects both early detection analysis and postmortem diagnoses of pathology. This chapter discusses molecular tools available for distinguishing different forms of misfolded protein assemblies, focusing mainly on small-molecule probes, including oligothiophenes sensitive to protein conformation.