Inhibition studies on aggregation and cytotoxicity of Alzheimer's amyloid-β peptide.

Abstract

Aberrant protein aggregation is associated with several, yet incurable neurodegenerative diseases including Alzheimer's and Parkinson's disease. Research of the last decade revealed that aggregation is the inherent property of the polypeptide chains and under non-physiological, appropriate conditions most of the proteins can aggregate and form polymers of various structures. However, our knowledge is scarce on the mechanisms that inhibit protein aggregation and there are only few molecules known that have an inhibitory effect on aggregation. We have been tested the effect of 13 in-house-designed inhibitor candidates in the size range of 500-1300 Da on the aggregation of amyloid-beta peptide (Aβ42) and on the structure and stability of the aggregates by various biophysical and spectroscopic methods (ThT fluorescence assay and TEM for aggregation, NMR measurements for interaction). These amphiphilic compounds have good solubility and potential interaction sites for Aβ42. Beyond their direct effect on Aβ42 aggregation, the inhibitor molecules have been characterized by cytotoxicity test (MTT assay) on cell cultures and in the case of promising candidates that were proved to be effective, in vivo in animal models. Many of the inhibitors or their by-products were found to be cytotoxic, however, we were able to sort out candidates that prevented Aβ42 cytotoxicity and have no harmful effect at the examined concentration ratio in vivo. These molecules can be promising candidates for further studies to work out effective therapies for neurodegenerative diseases in the future. Acknowledgements: This work has been carried out in collaboration of the Hungarian and Korean research groups supported bilaterally by the National Research, Development and Innovation Fund of Hungary (grant 2018-2.1.17-TÉT-KR-2018-00008 to J.K.) and the National Research Foundation of Korea (grant NRF-2018K1A3A1A39088040 to Y.-H.L.).