Alzheimer’s Disease (AD) is a genetic-based neurodegenerative disorder characterized by progressive impairment in memory. The hallmark of AD is the presence of amyloid-beta peptide in senile plaques and the presence of neurofibrillary tangles composed of tau.[1] The amyloid-beta plaques are generated by the self-assembling of the monomers into supramolecular nanofibrillar structures stabilized by the peptide’s beta-sheets. It is also accompanied by an impairment in the cellular redox status that leads to oxidative stress.

The beta-sheet breaking capacity of the natural polyphenols (presenting pyrogallol and galloyl moieties) have been tested to block the amyloid-beta self-assembling process, leading to the formation of non-fibrillar and non-toxic amyloid-beta aggregates. Another advantage of these compounds is their known antioxidant capacity, that can be used to stabilize the cellular redox status, making them as multifunctional compounds able to act directly at both the aggregation process and at the oxidative stress levels, protecting the AD patients’ against neuronal loss [2].

We have been working with purified natural polyphenols extracted from cork (e.g. castalagin and vescalagin) and we tested them for their antioxidant activity and capacity to inhibit the fibrillization of amyloid-beta. We found that these polyphenols display antioxidant activity and are able to inhibit amyloid-beta fibrillization. We confirmed their capacity of maintain SH-SY5Y cell viability under oxidative environment (i.e. hydrogen peroxide). In addition, their capacity to reduce the fibrillization of amyloid-beta was confirmed by atomic force microscopy (AFM), circular dichroism (CD) and isothermal calorimetry (ITC). Cell studies revealed their capacity to retain cellular activity in the presence of cytotoxic concentrations of amyloid-beta due to the reduced formation of nanofibers and increased deposition of the peptide into non-toxic aggregates.

Overall, our results demonstrate that the natural polyphenols, vescalagin and castalagin, present anti-oxidant activity, as well as, the capacity to inhibit the fibrillization of amyloid-beta. In general, they are promising candidates for the treatment of neurodegenerative disorders, in particular AD.

ACKNOWLEDGEMENTS: Authors acknowledge the financial support from Projeto “NORTE-08-5369-FSE-000037”, financed by Programa Operacional Norte 2020. This work was also supported by the European Union H2020, grant numbers H2020-TWINN-2015-692333 – CHEM2NATURE and H2020-WIDESPREAD-2014-2-668983 – FORECAST.

BIBLIOGRAPHY: 1.            Porat, Y., A. Abramowitz, and E. Gazit, Inhibition of amyloid fibril formation by polyphenols: structural similarity and aromatic interactions as a common inhibition mechanism. Chem Biol Drug Des, 2006. 67(1): p. 27-37.

2.            Mangialasche, F., et al., Alzheimer's disease: clinical trials and drug development. The Lancet Neurology, 2010. 9(7): p. 702-716.