Biphasic modulation of Aβ(1–40) self-assembly by porphyrins: effects of concentration and structural variation

Abstract

Aβ peptides self-assemble into senile plaques, a hallmark of Alzheimer’s disease (AD). The search for compounds able to modulate peptide self-assembly still await molecular and structural insights. In the present work, we have investigated a series of cationic porphyrins. By monitoring the kinetics of peptide self-assembly by thioflavin T (ThT) fluorescence and by imaging the assemblies formed using TEM and AFM, we observed : (i) first, some of them accelerate Aβ(1-40) self-assembly with an extent that increases with the porphyrin concentration. For the others, a relapse of the kinetic rates is observed above a concentration threshold (noted CM) that is porphyrin-dependent. The biphasic modulation thus observed has not been reported so far in case of porphyrins; (ii) second, the porphyrins decrease the level of Aβ(1-40) fibrils formed as their concentration increases. The interactions between the porphyrins and the Aβ(1-40) have been thoroughly characterized by UV-visible, NMR, and fluorescence spectroscopies. The obtained data support a structure-dependent model involving Pi-stacking, electrostatic and hydrophobic interactions, responsible for the different effects of the porphyrins on the Aβ(1-40) self-assembly.