@article {19756, title = {Galloyl-terminated dendrimers modulate Aβ42 fibrillization and reduces cellular toxicity}, booktitle = {13th EYCN Delegates Assembly }, year = {2018}, month = {2018-05-07 00:00:00}, address = {Torino, Italy}, abstract = {

Alzheimer{\textquoteright}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{\textquoteright}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.,Nat Rev Drug Discov, 2015. 14(11): p. 759-780.

[2] Meisl, G., et al.,Nat. Protocols, 2016. 11(2): p. 252-272.

[3] Attar, A., F. Rahimi, and G. Bitan, Trans Neuro, 2013. 4(4): p. 385-409.

}, keywords = {Alzheimer{\textquoteright}s disease, natural polyphenols}, author = {Ara{\'u}jo, A. R. and Correa, J. and Fernandez-Megia, E. and Reis, R. L. and Pires, R. A.} }