Investigating New Applications of a Photoswitchable Fluorescent Norbornadiene as a Multifunctional Probe for Delineation of Amyloid Plaque Polymorphism

Amyloid beta (AO') plaques are a major pathological hallmark of Alzheimer's disease (AD) and constitute of structurally heterogenic entities (polymorphs) that have been implicated in the phenotypic heterogeneity of AD pathology and pathogenesis. Understanding amyloid aggregation has been a critical limiting factor to gain understanding of AD pathogenesis, ultimately reflected in that the underlying mechanism remains elusive. We identified a fluorescent probe in the form of a turn-off photoswitchable norbornadiene derivative (NBD1) with several microenvironment-sensitive properties that make it relevant for applications within advanced fluorescence imaging, for example, multifunctional imaging. We explored the application of NBD1 for in situ delineation of structurally heterogenic AO' plaques in transgenic AD mouse models. NBD1 plaque imaging shows characteristic broader emission bands in the periphery and more narrow emission bands in the dense cores of mature cored plaques. Further, we demonstrate in situ photoisomerization of NBD1 to quadricyclane and thermal recovery in single plaques, which is relevant for applications within both functional and super-resolution imaging. This is the first time a norbornadiene photoswitch has been used as a probe for fluorescence imaging of AO' plaque pathology in situ and that its spectroscopic and switching properties have been studied within the specific environment of senile AO' plaques. These findings open the way toward new applications of NBD-based photoswitchable fluorescent probes for super resolution or dual-color imaging and multifunctional microscopy of amyloid plaque heterogeneity. This could allow to visualize AO' plaques with resolution beyond the diffraction limit, label different plaque types, and gain insights into their physicochemical composition.

Automated summary

A newly developed fluorescent probe, NBD1, has been used to visualize and study the structure and composition of senile plaques in Alzheimer's disease. This provides a new tool for investigating the pathological mechanism of Alzheimer's disease.