Sun_2019_Mar.Drugs_17_

beta-Amyloid (Abeta) is regarded as an important pathogenic target for Alzheimer's disease (AD), the most prevalent neurodegenerative disease. Abeta can assemble into oligomers and fibrils, and produce neurotoxicity. Therefore, Abeta aggregation inhibitors may have anti-AD therapeutic efficacies. It was found, here, that the marine-derived alkaloid, fascaplysin, inhibits Abeta fibrillization in vitro. Moreover, the new analogue, 9-methylfascaplysin, was designed and synthesized from 5-methyltryptamine. Interestingly, 9-methylfascaplysin is a more potent inhibitor of Abeta fibril formation than fascaplysin. Incubation of 9-methylfascaplysin with Abeta directly reduced Abeta oligomer formation. Molecular dynamics simulations revealed that 9-methylfascaplysin might interact with negatively charged residues of Abeta42 with polar binding energy. Hydrogen bonds and pi(-)pi interactions between the key amino acid residues of Abeta42 and 9-methylfascaplysin were also suggested. Most importantly, compared with the typical Abeta oligomer, Abeta modified by nanomolar 9-methylfascaplysin produced less neuronal toxicity in SH-SY5Y cells. 9-Methylfascaplysin appears to be one of the most potent marine-derived compounds that produces anti-Abeta neuroprotective effects. Given previous reports that fascaplysin inhibits acetylcholinesterase and induces P-glycoprotein, the current study results suggest that fascaplysin derivatives can be developed as novel anti-AD drugs that possibly act via inhibition of Abeta aggregation along with other target mechanisms.