Reversing Aβ Fibrillation and Inhibiting Aβ Primary Neuronal Cell Toxicity Using Amphiphilic Polyphenylene Dendrons

Abstract

Uncontrolled amyloid-beta (A𝜷) fibrillation leads to the deposition of neurotoxic amyloid plaques and is associated with Alzheimer's disease. Inhibiting A𝜷 monomer fibrillation and dissociation of the formed fibers is regarded as a promising therapeutic strategy. Here, amphiphilic polyphenylene dendrons (APDs) are demonstrated to interrupt A𝜷 assembly and reduce A𝜷-cell interactions. Containing alternating negatively charged sulfonic acid and hydrophobic n-propyl peripheral groups, APDs bind to the secondary structure of the A𝜷 aggregates, inhibiting fibrillation and disassemble the already formed A𝜷 fibrils. APDs reveal vesicular cellular uptake in endosomes as well as cell compatibility for endothelial and neuronal cells, and significantly reduce A𝜷-induced neuron cytotoxicity in vitro. Moreover, they are transported into the brain and successfully cross the blood-brain barrier after systemic application in mice, indicating their high potential to inhibit A𝜷 fibrillation in vivo, which can be beneficial for developing therapeutic strategy for Alzheimer's disease.

Adaptive Synthesis of Functional Amphiphilic Dendrons as a Novel Approach to Artificial Supramolecular Objects

“…For example, amphiphilic fluorescent phosphorus dendron-based micelles formed in aqueous solutions possessed diameters of approximately 30-40 nm [19]. Similar sizes (~50 nm) were observed in solutions of thermosensitive poly(benzyl ether) dendrons [66], as well as for amphiphilic-polyphenylene-dendronized proteins [67].…”

Engineering surface patterns on nanoparticles: new insights into nano-bio interactions

“…Surprisingly, by optimising the hydrophilic and hydrophobic patterns on the surface, these PPDs could be efficiently taken up by cells and even able to penetrate blood brain barrier models without affecting the membrane integrity. 177 PPDs form 3D spheroids in aqueous solution with lipophilic cavities inside (like a protein structure).…”

Photoinduced Amyloid Fibril Degradation for Controlled Cell Patterning

“…Changing environmental parameters such as peptide concentration and pH can lead to disassembly, as these parameters affect the equilibrium of fibril formation. 31 Furthermore, additives such as ruthenium(II)-complexes, 32 fullerenes, 33 water-ethanol mixtures, 34 amphiphilic polyphenylene dendrimers, 35 PEG-chains, 36 carbon nanotubes, 37 and molecular chaperons 38,39 have been applied to disassemble amyloid fibrils. However, these methods cannot be applied for controlled spatiotemporal modification after fibrils are embedded in complex environments.…”

“…o-Nitrobenzyl ester is a well-established photoresponsive molecule and compatible with self-assembling peptides. 4,28,[33][34][35] Using this photocleavable linker (PCL) attached to amyloid-like fibrils, we previously created functional cell-gradients by photocleavage of a bioactive moiety from the fibrillar backbone. 49 It is important to note that in this published report, the fibrillar backbone of the nanofibrils remained intact and also cell-adherent to some extent, limiting the generation of unique cell patterns.…”