Caffeic acid for the prevention and treatment of Alzheimer's disease: The effect of lipid membranes on the inhibition of aggregation and disruption of Aβ fibrils.

Abstract The onset of Alzheimer's disease (AD) is triggered by the aggregation of amyloid β (Aβ) peptides which leads to the formation of fibrils. Molecules that are able to inhibit fibrillation and/or disrupt fibrils have aroused interest for AD therapy. Fibrillation is a complex process highly dependent on the surrounding environment. One of the most relevant factors affecting Aβ aggregation is the presence of cellular membranes. Here, the ability of caffeic acid (CA) in preventing the Aβ1-42 aggregation and disaggregating mature fibrils was evaluated in a membrane-like environment and in a bulk solution for comparison. To this end, liposomes were used as in vitro models of neuronal membranes. CA exhibited strong activity in inhibiting the fibrillation of Aβ1-42 in the aqueous medium, which remained in the presence of liposomes. Furthermore, CA disrupted instantly preformed fibrils in the aqueous medium. However, the CA's disaggregating activity was disturbed by the presence of lipid membranes. Instead of being immediate, the CA's disaggregating activity increased over time. The moderate affinity of CA for the lipid bilayer may explain the distinct fibrils disaggregation profiles. These findings emphasize the therapeutic potential of CA in preventing and treating AD, thus justifying further investigations in animal models.