Stilbenes: Therapeutic Interventions Targeting Amyloid beta Protein Aggregation In Alzheimer's Diseas

Alzheimer's disease (AD) is the most common form of dementia and accounts for 60-80 % of all dementia cases. In the United States, AD is ranked as the 6th leading cause of death and it is the only one among the top 10 that cannot be prevented, treated or even slowed. All FDA approved drugs focus on attenuating the symptoms for a limited time by regulating neurotransmitters without any intervention with the underlying disease process. A major player in the initiation and development of this debilitating disorder is the misfolding and subsequent aggregating of amyloid-beta (Abeta) peptide. This aggregation process converts non-toxic functional Abeta peptides into a spectrum of neurotoxic Abeta aggregated species, such as, oligomers, soluble aggregates and fibrils. These aggregated forms are believed to be the source of inflammation and oxidative stress that cause neuron death and the loss of synaptic functions. Therefore, small molecules that could intervene with the aggregation of Abeta peptides may present an effective AD therapeutic prevention and treatment.;The work presented here examined the intervening effects of eight stilbenes, such as resveratrol and piceatannol, on multiple mechanistic steps of Abeta aggregation. Results identified trans-piceatannol and cis-piceatannol as the most potent compounds that could affect distinct aggregation pathways, specifically, modifying the conformation of Abeta aggregates, as well as, reducing soluble aggregate growth rate. The pronounced change in Abeta aggregate conformation might be related to a change in cytotoxicity. Their superior effects could be attributed to the presence of catechol moiety. The change in Abeta aggregate conformation induced by trans-piceatannol substantially reduced the Abeta aggregates binding to lipid bilayers, which plays a vital role in the induction of neurotoxicity. Other stilbenes, including resveratrol, also altered the morphology of Abeta aggregates but they exhibited only moderate interfering effects on Abeta aggregation pathways. Together, this study provides insight into the effective interventions of piceatannol on Abeta aggregation and proposes this natural compound as a novel promising small molecule for the prevention and treatment of AD.