Branched KLVFF Tetramers Strongly Potentiate Inhibition of β‐Amyloid Aggregation

Abstract

The key pathogenic event in the onset of Alzheimer's disease (AD) is the aggregation of β‐amyloid (Aβ) peptides into toxic aggregates. Molecules that interfere with this process might act as therapeutic agents for the treatment of AD. The amino acid residues 16–20 (KLVFF) are known to be essential for the aggregation of Aβ. In this study, we have used a first‐generation dendrimer as a scaffold for the multivalent display of the KLVFF peptide. The effect of four KLVFF peptides attached to the dendrimer (K4) on Aβ aggregation was compared to the effect of monomeric KLVFF (K1). Our data show that K4 very effectively inhibits the aggregation of low‐molecular‐weight and protofibrillar Aβ1–42 into fibrils, in a concentration‐dependent manner, and much more potently than K1. Moreover, we show that K4 can lead to the disassembly of existing aggregates. Our data lead us to propose that conjugates that bear multiple copies of KLVFF might be useful as therapeutic agents for the treatment of Alzheimer's disease.

Reduced Aggregation and Cytotoxicity of Amyloid Peptides by Graphene Oxide/Gold Nanocomposites Prepared by Pulsed Laser Ablation in Water

“…Aβ is assembled into fi brillar β-amyloid due to intracellular β-amyloid precursor protein (APP) in the neuronal membrane by the secretase complex. [ 3,7 ] The inhibitors of Aβ peptide fi brillization have been developed from peptides, [ 8 ] antibodies, [ 9 ] molecules [ 10 ] to nanomaterials. [ 11,12 ] The advantage of nanomaterials is mainly focused on the high surface ratio and facilitation of multifunctions.…”

Nanomaterials in Stroke Treatment

“…31 Different generations of poly(amidoamine) (PAMAM) dendrimers and both polypropylenimine and phosphorus dendrimers have been used successfully to disaggregate amyloid fibrils under different conditions. [31][32][33][34][35][36] Also, PAMAM dendrimers inhibited the fibrillation of α-synuclein, and this effect increased with both generation number and PAMAM concentration. [37][38][39] Among all nanomaterials discussed, dendrimers showed themselves the least toxic.…”

Adding Functions to Biomaterial Surfaces through Protein Incorporation

“…[68] This occurs under physiological conditions via the formation of a thioester bond between cysteine residues in the protein and support material, followed by spontaneous rearrangement of a S→N acyl shift to form the peptide bond at the ligation site. NCL has been used in a variety of studies to bioconjugate oligopeptides and recombinant proteins to dendrimers [69] as the approach allows chemo-selective dendrimer conjugation to many proteins without interfering with their activities. Hyperbranched polymers obtained from poly(propyleneimine) have also been modified with succinimide-activated cysteine residues to yield first, second and third generation dendrimers with 4, 8 and 16 cysteine end-groups, respectively, providing templates for conjugation of multiple protein copies for increased valency or higher sensitivity in bioassays.…”