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

Uncontrolled amyloid-beta (A beta) fibrillation leads to the deposition of neurotoxic amyloid plaques and is associated with Alzheimer's disease. Inhibiting A beta monomer fibrillation and dissociation of the formed fibers is regarded as a promising therapeutic strategy. Here, amphiphilic polyphenylene dendrons (APDs) are demonstrated to interrupt A beta assembly and reduce A beta-cell interactions. Containing alternating negatively charged sulfonic acid and hydrophobic n-propyl peripheral groups, APDs bind to the secondary structure of the A beta aggregates, inhibiting fibrillation and disassemble the already formed A beta fibrils. APDs reveal vesicular cellular uptake in endosomes as well as cell compatibility for endothelial and neuronal cells, and significantly reduce A beta-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 A beta fibrillation in vivo, which can be beneficial for developing therapeutic strategy for Alzheimer's disease.