Mixed Carboxyl and Hydrophobic Dendrimer Surface Inhibits Amyloid-β Fibrillation: New Insight from the Generation Number Effect

Abstract

Fibrillation of amyloid-β peptide (Aβ) is closely associated with the progression of Alzheimer’s disease (AD), and so inhibition of Aβ fibrillation has been considered as one of the promising strategies for AD prevention and treatment. Our group has proposed the hydrophobic binding-electrostatic repulsion (HyBER) theory on inhibiting Aβ fibrillation by a surface with mixed negative charges and hydrophobic groups, which provides a new strategy for the design of potent amyloid inhibitors. Carboxyl-terminated polyamidoamine dendrimer (PAMAM) is a kind of biocompatible nanomaterial with only carboxyl groups on its surface, and its architecture and property vary with the generation number, low-generation dendrimers possessing sparse distributions of terminal groups while high-generation dendrimers having compact surface groups, which offer abundant base materials for further study of the HyBER theory. We have designed a potent amyloid inhibitor with generation 5 PAMAM. To provide new insights into the HyBER mechanism, we have herein proposed to synthesize phenyl-modified PAMAM dendrimers of generations 3 to 6 (G3-P to G6-P) and study the effect of the generation number on Aβ fibrillation. Results show that phenyl derivatives of low-generation dendrimers (G3-P and G4-P) do not show any interference with Aβ aggregation, whereas the phenyl derivatives of high-generation dendrimers (G5-P and G6-P) significantly inhibit Aβ42 aggregation and alter the ultrastructure of Aβ42 aggregates. The results indicate that the density and distribution of surface functional groups on a dendrimer is of great importance for the HyBER effect to happen. The new understanding on the HyBER mechanism would benefit in the development of potent amyloid inhibitors based on the theory.

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

“…As depicted in Figure 4D, the A𝛽 monomers exhibited a negative peak around 198 nm, indicating the random coil structure. [24] For A𝛽 fibrils, the negative peak disappeared and new peaks (a maximum ellipticity at around 198 nm and a minimum in the ellipticity at 216 nm) were observed, proving that the random structure of the peptide was converted to 𝛽-sheets as reported previously. [25] After incubating D and A𝛽 monomers at 4:3 (D:A𝛽) ratio, a maximum ellipticity at 198 nm was still observed, but with lower intensity than A𝛽 fibril alone, suggesting that A𝛽 still partially formed the 𝛽-sheets (Figure 5A, yellow line).…”

“…Upon binding, the repulsion between the negatively charged sulfonate groups of dendrons and the anionic peptide residues could induce the observed unfolding and defibrillation of the A𝛽 peptide. [24] Furthermore, the aromatic amino acids of A𝛽 could interact with the aromatic groups of D by 𝜋-𝜋 stacking, which could inhibit fibrillation and 𝛽-sheet formation of A𝛽. [24] In order to further elucidate the broader application of amphiphilic dendrons, we have studied the impact on another amyloid-like peptide, Fmoc-ISA (Figure S12A the disassembly of Fmoc-ISA fibrils.…”

“…[24] Furthermore, the aromatic amino acids of A𝛽 could interact with the aromatic groups of D by 𝜋-𝜋 stacking, which could inhibit fibrillation and 𝛽-sheet formation of A𝛽. [24] In order to further elucidate the broader application of amphiphilic dendrons, we have studied the impact on another amyloid-like peptide, Fmoc-ISA (Figure S12A the disassembly of Fmoc-ISA fibrils. The corresponding TEM image also proved that no fibrils but only residual amorphous structures were imaged after subsequent addition of D to the Fmoc-ISA solution (Figure S12C, Supporting Information).…”

The Membrane Axis of Alzheimer's Nanomedicine

“…[ 157 ] Wang et al developed high generations of phenyl‐modified carboxyl‐terminated polyamidoamine (PAMAM) dendrimers, with the capability of inhibiting Aβ42 aggregation and altering the ultrastructure of Aβ42 aggregates via the hydrophobic binding‐electrostatic repulsion (HyBER) theory. [ 158 ] Aβ‐targeting ligand conjugation on nanoparticles is an efficient approach for disrupting the amyloidogenic process. Aβ‐binding peptide Lys‐Leu‐Val‐Phe‐Phe (KLVFF) integrated with polymeric nanocomposites (NC‐KLVFF) remarkably eliminated toxic Aβ aggregates, regained endocranial microglia's capability to phagocytose the peptide, and protected hippocampal neurons against apoptosis in AD mice ( Figure 8 ).…”

Small-Molecule-Functionalized Hyperbranched Polyglycerol Dendrimers for Inhibiting Protein Aggregation

“…Proteins have a specific three-dimensional (3D) (tertiary) structure mostly held together by multiple weak interactions and any discrepancy in their 3D conformation leads to structural collapse with the possibility to form aggregates both extra-/intracellularly. − Different kinds of neurodegenerative diseases are associated with particular protein misfolding, amyloid aggregation, and disruption of the normal neuronal activity. For example, Alzheimer’s disease occurs because of the formation of amyloid-β-protein aggregation. , Similarly, in Huntington’s disease (HD), the mutated gene produces abnormal huntingtin protein, which forms intracellular aggregates, leading to severe motor disturbances. , Thus, the inhibition of protein aggregation and clearance of amyloid aggregates from neuronal cells are the main therapeutics strategies for neurodegenerative diseases. − Most of the small molecules (or antiamyloidogenic molecules) that prevent protein aggregation are naturally occurring polyphenols, − carbohydrates, and peptides. , Moreover, synthetic molecules − and biomolecules, , star polymers, functional inorganic nanoparticles, , polymer nanoparticles, − and dendrimers − have been used to investigate the antiamyloidogenic property. We have recently shown that the nanoparticle form of small molecules shows better antiamyloidogenic performance because of enhanced bioavailability and multivalent binding with protein. − This result has encouraged us to design biodegradable/biocompatible forms of nanoparticles with the surface terminated with antiamyloidogenic small molecules .…”