Aging is one of the main factors that lead to the increase in the prevalence of neurodegenerative disorders, e.g. Alzheimer Disease (AD). AD is characterized by the occurrence of extracellular senile plaques of aggregated amyloid-beta peptide (Ab42), leading to neural loss and memory impairment.

These plaques are generated by the self-assembling of Ab42 monomers into supramolecular nanofibrillar structures stabilized by the peptide’s β-sheets. The intracellular soluble Ab42 oligomers, the precursors of the senile plaques, are reported to be the main cause of its toxicity [1].

We have previously demonstrated (unpublished data) that the use of natural polyphenols can reduce cell death, promoted by the Ab42 monomers/oligomers/fibrils. In fact, the use of EGCG as a modulator of Ab42 self-assembly has beenreported. [2] The ability of EGCG to block the assembly process has been ascribed to the interference in the Pi-Pi stacking of the aromatic rings from the phenylalanine residues within the Ab42 supramolecular arrangement [3]. Overall, most of the natural polyphenols that have been reported to modulate Ab42 self-assembly present galloyl-type moieties. Based on this observation, we designed dendrimers displaying this type of moieties on their surface and tested them for their ability to modulate Ab42 fibrillization.

We synthesized G0-GA core dendrimer with two gallates, and a G1-GA with six gallate groups. We used Circular dichroism and fluorescence spectroscopy to evaluate their ability to inhibit Ab42 fibrillization. Our results show that G1-GA is able to modulate the β-sheet content of the Ab42 supramolecular assemblies, while reducing the size of the fibrils. We also confirmed that G1-GA has the capacity of maintain SH-SY5Y cell viability, reducing the oligomeric Aβ42 assemblies in the cytoplasm of the cells. Our results demonstrate that G1-GA dendrimer represents a promising custom-made nanotherapeutical tool able to modulate the toxicity of Ab42 assemblies in the AD context.