Interrogating Amyloid Aggregates using Fluorescent Probes

Abstract

Amyloids are a broad class of proteins and peptides that can misfold and assemble into long unbranched fibrils with a cross-β conformation. These misfolding and aggregation events are associated with the onset of a variety of human diseases, among them, Alzheimer’s disease, Parkinson’s disease, and Huntington disease. Our understanding of amyloids has been greatly supported by fluorescent molecular probes, such as thioflavin-T, which shows an increase in fluorescence emission upon binding to fibrillar aggregates. Since the first application of thioflavin-T in amyloid studies nearly 30 years ago, many probes have emerged exhibiting a variety of responses to amyloids, such as intensity changes, shifts in fluorescence maxima, and variations in lifetimes, among many others. These probes have shed light on a variety of topics including the kinetics of amyloid aggregation, the effectiveness of amyloid aggregation inhibitors, the elucidation of binding sites in amyloid structures, and the staining of amyloids aggregates in vitro, ex vivo, and in vivo. In this Review, we discuss the design, properties, and application of photoactive probes used to study amyloid aggregation, as well as the challenges faced by current probes and techniques, and the novel approaches that are emerging to address these challenges.

Differentiating Aβ40 and Aβ42 in amyloid plaques with a small molecule fluorescence probe

“…Our design strategy is different from most previous studies, which are focused on adjusting optical properties to turn on (off) signals or make larger stokes shis. [9][10][11][12][13] Unfortunately, few probes have been designed based on the insights from the Ab structures. In this report, we demonstrated that our designed small-molecule uorescence probe, ICTAD-1, has the capacity to spectrally differentiate Ab40 and Ab42 in vitro and in the biologically relevant environment.…”

Self‐Reporting of Folding and Aggregation by Orthogonal Hantzsch Luminophores Within a Single Polymer Chain

“…Well‐known examples are Alzheimer's, Parkinson's and Huntington's diseases [2] . To better understand diseases and design drugs, a variety of methods—from biochemical assays to time‐resolved microscopy—have been developed to investigate protein folding [3] and to monitor the self‐assembly of defective proteins into pathogenic protein aggregates [4] . Among them, photoluminescence techniques are highly valuable due to their high sensitivity and the possibility to select, synthesize and optimize a diversity of photoluminescence probes (luminophores).…”

Rationally Designing Simple Rod-Like Amphiphilic NIR-Emissive AIE Probes for Precise In-Vivo Detection of Aβ Fibrils/Plaques at A Super-Early Stage

“…Based on the analysis above, we sort out four main criteria which should be satisfied to realize high-performance fluorescent probes for detecting and imaging Aβ fibrils and plaques in vivo at an early stage (Scheme 1B): (1) geometric configurations matching the β-sheet structure; (2) balanced hydrophilicity and hydrophobicity which guarantees the BBB crossing ability and high SNR;…”