General Aggregation-Induced Emission Probes for Amyloid Inhibitors with Dual Inhibition Capacity against Amyloid β-Protein and α-Synuclein

Abstract

Amyloid self-assembly is pathologically linked to many neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). While many inhibitors have been developed individually for specific amyloid proteins, there are a few effective platforms to screen on a large scale general amyloid inhibitors against different amyloid proteins. Herein, we developed a new class of amyloid inhibitor probes by site-specific conjugation of aggregation-induced emission (AIE) molecules with amyloid proteins (i.e., AIE@amyloid probes) to realize a high-throughput screening of small-molecule inhibitors. Optimization of site-specific AIE conjugation with two amyloid proteins, amyloid-β protein (Aβ) and α-synuclein (αSN), enabled us to retain their high amyloidogenic properties; i.e., AIE-amyloid probes alone exhibited strong fluorescence due to amyloid-like aggregation, but they showed no fluorescence in the presence of amyloid inhibitors to prevent amyloid aggregation. From integration of AIE@amyloid probes and computational virtual screening from a large drug database, it was found that tolcapone possessed a dual inhibition against the aggregation and cytotoxicity of both Aβ and αSN. More importantly, tolcapone significantly improved the spatial cognition and recognition of Aβ-treated mice. This work represents an innovative attempt to design an AIE-based anti-amyloid drug platform for identifying new small-molecule inhibitors against amyloidogenesis in both AD and PD or other amyloid diseases.

Advances in aptamers against Aβ and applications in Aβ detection and regulation for Alzheimer's disease

“…Meanwhile, researchers have also made many efforts to develop amyloid aggregation inhibitors in order to promote the therapy of AD. They have discovered kinds of Aβ aggregation-regulated molecules and nanomaterials by exploring the interaction between amyloid and antibodies 33 - 38 , peptides 39 - 44 , small molecules 45 - 51 , aptamers 52 - 56 , polymers 57 - 59 , as well as nanomaterials 60 - 63 . Most of these inhibitors can regulate the aggregation process of Aβ in vitro or in vivo and reduce the cytotoxicity caused by Aβ aggregates to a certain extent, providing a valuable treatment strategy for delaying AD progression.…”

Dual functional amphiphilic sugar-coated AIE-active fluorescent organic nanoparticles for the monitoring and inhibition of insulin amyloid fibrillation based on carbohydrate–protein interactions

“…25 So far, several studies associated with AIE have been reported on the detection of amyloid fibrils including insulin, Ab 42 and lysozyme. 17,[26][27][28][29][30][31][32][33][34][35][36] Due to their highly emissive properties in supramolecular assembly and the supramolecular assembly of amyloid monomers into fibrils, these kinds of probes are quite suitable for fibril detection. However, there were a few fluorescent probes that can monitor the content of fibril aggregates and also had inhibition effects on protein amyloidosis.…”

Dual-targeted carbon-dot-drugs nanoassemblies for modulating Alzheimer's related amyloid-β aggregation and inhibiting fungal infection

“…Currently, most of A β inhibitors including biomolecules [ [23] , [24] , [25] , [26] ], functionalized nanomaterials and nanoparticles [ 16 , 17 , [27] , [28] , [29] , [30] , [31] ], have been shown to decelerate the aggregation of A β and suppress cellular toxicity of amyloid. For example, Sun et al.…”