Functional Gallic Acid-Based Dendrimers as Synthetic Nanotools to Remodel Amyloid-β-42 into Noncytotoxic Forms

The self-assembly of amyloid-beta (A beta) generates cytotoxic oligomers linked to the onset and progression of Alzheimer's disease (AD). As many fundamental molecular pathways that control A beta A beta aggregation are yet to be unraveled, an important strategy to control cytotoxicity is the development of bioactive synthetic nanotools capable of interacting with the heterogeneous ensemble of A beta species and remodel them into noncytotoxic forms. Herein, the synthesis of nanosized, functional gallic acid (Ga)-based dendrimers with a precise number of Ga at their surface is described. It is shown that these Gaterminated dendrimers interact by H-bonding with monomeric/oligomeric A beta species at their Glu, Ala, and Asp residues, promoting their remodeling into noncytotoxic aggregates in a process controlled by the Ga units. The multivalent presentation of Ga on the dendrimer surface enhances their ability to interact with Afi, inhibiting the primary and secondary nucleation of A beta fibrillization and disrupting the Afi preformed fibrils.

Automated summary

In this study, the synthesis of nanosized, functional gallic acid-based dendrimers is described, which interact with Aβ species and remodel them into noncytotoxic aggregates. The multivalent presentation of gallic acid on the dendrimer surface enhances their ability to interact with Aβ, inhibiting fibrillization and disrupting preformed fibrils.