New fluorescent molecular probes for ex vivo assessment of neurodegenerative protein conformational pathology

Therapeutic interventions’ lackluster performance in Alzheimer dementia (AD) may in part be due to the irreversibly advanced stage of the pathological process underlying cognitive decline once the latter is diagnosed. Currently, clinical diagnosis of AD is supported by in vivo molecular imaging of disease-related Aβ and Tau aggregates in the brain, and analysis of cerebrospinal fluid. Positron Emission Tomography, Single Photon Emission Computed Tomography, and Magnetic Resonance imaging are the most common methods used. They are costly, which limits their use in routine screening. We used fluorescent microscopy to examine and compare the selectivity and optical properties of small fluorescent molecules, designed to translate subtle changes in their environment to their optical properties upon binding to AD biomarkers including amyloid-beta and Tau protein. In addition, we investigated their affinity for other targets, including Lewy and Pick bodies, using brain tissue samples obtained post mortem from patients with confirmed AD, a familial tauopathy with Tau mutation, Parkinson disease, and Pick disease, and cross-referenced our findings with immunofluorescence staining. We found that several probes, primarily designed to bind AD biomarkers, also exhibit affinity for intra- and extracellular Tau deposits, as well as Lewy and Pick bodies, and can be used to distinguish various types of pathology based on emission spectra. While our long-term goal is the development of reliable and cost-effective molecular probes to detect conformational pathology in blood samples, our presentation will focus on comparative characteristics of the four canditate probes in fluorescent microscopy of post mortem brain tissue samples.