Natural aromatic small molecules redesign toxic soluble Aβ42 oligomers

INTRODUCTION: Aging and oxidative stress are the main triggers of supramolecular self-assembly of amyloidogenic proteins, such as Amyloid β (1-42), the hallmark of Alzheimer Disease. [1, 2]. Herein, we attempted to evaluate the influence of antioxidant aromatic small molecules (polyphenols) on the redesign/inhibition of Aβ42 peptide and within a reduction of ROS species caused by AD.

METHODS: Polyphenols vescalagin/castalagin were extracted from the outer bark of Quercus S. powder. The capacity of these small molecules to modulate the Aβ42 fibrillization was evaluated by CD, Thioflavin T, STEM, and AFM. The antioxidant potential was accessed by DPPH assay and DCFH-DA dye with H₂O₂.

Cell studies were conducted with SHSY-5Y neuroblastoma cell line. The evaluation of the capacity to decrease the cytotoxic of these events was performed with Live/dead staining, alamarBlue® assay, and immunocytochemistry

RESULTS: CD and Thioflavin T measurements revealed a remodeling of the Aβ42 peptide through inhibition of the oligomers/monomers self-assembly and disassembling after the addition of these polyphenols. STEM and AFM images (Fig1-A) showed a redesign and a significant decrease in the Aβ42 peptide fibrils size. DCFH-DA dye results showed the ability of these molecules decrease ROS species, promoting at the same time, the diminution of toxic oligomers/fibrils in culture conditions - by Live/dead assay and alamarBlue® assay. Immunostaining showed a significant decrease in 6E10 antibody fluorescence.

DISCUSSION & CONCLUSIONS: Both molecules are able to interfere in the aggregation process of Aβ peptides and rescue cells from oxidative stress (H₂O₂) diminishing the toxicity promoted through the spreading of Aβ42 monomers/oligomers.

ACKNOWLEDGEMENTS: Financial support from NORTE-08-5369-FSE-000037 OP Norte 2020"; EU-H2020-TWINN-2015-692333-CHEM2NATURE, H2020-WIDESPREAD-2014-2-668983-FORECAST.

REFERENCES

1] Eisele, Y.S., et al.Nat Rev Drug Discov, 2015. 

[2] Meisl, G., et al.,Nat. Protocols, 2016. 11(2).