Alzheimer's disease (AD) is characterized by the occurrence of extracellular senile plaques of aggregated amyloid-beta peptide (Ab42). These plaques are generated by the self-assembling of Ab42 monomers into supramolecular nanofibrillar structures stabilized by the peptide’s β-sheets. While the senile plaques are a hallmark of AD, the presence of intracellular soluble Ab42 oligomers (precursors of the senile plaques) are reported to be the main cause of its toxicity [1]

We have previously demonstrated that the use of natural polyphenols can rescue cell viability affected by the Ab42 fibrillization. In fact, the use of EGCG as a modulator of Ab42 self-assembly has been studied, and its ability to block the assembly process has been reported [2]. The activity of EGCG is reported to occur through the interference of the Pi-Pi stacking within the Ab42 supramolecular arrangement [3]. In general, most of the natural polyphenols 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 synthesised a G0-GA core dendrimer with two gallates, and a G1-GA one with six gallate groups. We used CD, DLS and fluorescence spectroscopy to evaluate their ability to inhibit Ab42 fibrillization. Our results show that G1-GA is able to decrease 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.

REFERENCES:

1.            Eisele, Y.S., et al., Targeting protein aggregation for the treatment of degenerative diseases. Nat Rev Drug Discov, 2015. 14(11): p. 759-780.

2.            Meisl, G., et al., Molecular mechanisms of protein aggregation from global fitting of kinetic models. Nat. Protocols, 2016. 11(2): p. 252-272.

3.            Attar, A., F. Rahimi, and G. Bitan, Modulators of Amyloid Protein Aggregation and Toxicity: Egcg and Clr01. Translational Neuroscience, 2013. 4(4): p. 385-409.