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.