The abnormal deposition of Aβ amyloid deposits in the brain is a hallmark of Alzheimer's disease (AD). Based on this evidence, many current therapeutic approaches focus on the development of small molecules halting Aβ aggregation. However, due to the temporary and elusive structures of amyloid assemblies, the rational design of aggregation inhibitors remains a challenging task. Here we combine ThT assays and MD simulations to study Aβ aggregation in the presence of the natural compounds tyrosol (TY), 3-hydroxytyrosol (HDT), and 3-methoxytyrosol (homovanillyl alcohol - HVA). We show that albeit HDT is a potent inhibitor of amyloid growth, TY and HVA catalyze fibril formation. An inspection of MD simulations trajectories revealed that the different effects of these three molecules on Aβ1-40 aggregation are ascribable to their capacity to arrange H-bonds network between the ligand (position C-3) and the peptide (Glu22). We believe that our results may contribute to the design of more effective and safe small molecules able to contrast pathogenic amyloid aggregation.

Consiglio Nazionale delle Ricerche Istituto di Cristallografia Via Paolo Gaifami 18 95126 Catania Italy

Department of Agriculture and Forest Science University of Tuscia Via S Camillo De Lellis 01100 Viterbo Italy

Department of Chemical Sciences University of Naples Federico 2 Via Cintia 4 1 80126 Napoli Italy

Heidelberg University Biochemistry Center Im Neuenheimer Feld 328 69120 Heidelberg Germany; Department of Physics University of Helsinki P O Box 64 FI 00014 Helsinki Finland

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovonám 542 2 CZ 16610 Prague Czech Republic

Citace poskytuje Crossref.org

Synthesis of Ethylphosphonate Curcumin Mimics: Substituents Allow Switching Between Cytotoxic and Cytoprotective Activities