Abstract
β-Amyloid (Aβ) is regarded as an important pathogenic target for Alzheimer’s disease (AD), the most prevalent neurodegenerative disease. Aβ can assemble into oligomers and fibrils, and produce neurotoxicity. Therefore, Aβ aggregation inhibitors may have anti-AD therapeutic efficacies. It was found, here, that the marine-derived alkaloid, fascaplysin, inhibits Aβ 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 Aβ fibril formation than fascaplysin. Incubation of 9-methylfascaplysin with Aβ directly reduced Aβ oligomer formation. Molecular dynamics simulations revealed that 9-methylfascaplysin might interact with negatively charged residues of Aβ42 with polar binding energy. Hydrogen bonds and π–π interactions between the key amino acid residues of Aβ42 and 9-methylfascaplysin were also suggested. Most importantly, compared with the typical Aβ oligomer, Aβ 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-Aβ 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 Aβ aggregation along with other target mechanisms.
Highlights
Alzheimer’s disease (AD) is a chronic and debilitating neurodegenerative disease that normally occurs in the elderly
The present study has shown that fascaplysin can directly inhibit Aβ fibrillization in vitro. 9-Methylfascaplysin more potently inhibited Aβ fibrillization than fascaplysin
By using this in vitro system, it was found that fascaplysin (3–10 μM) slightly, but statistically significantly, inhibits the formation of Aβ fibrils
Summary
Alzheimer’s disease (AD) is a chronic and debilitating neurodegenerative disease that normally occurs in the elderly. AD is clinically characterized by cognitive impairments, mainly due to the loss of. Mar. Drugs 2019, 17, 121; doi:10.3390/md17020121 www.mdpi.com/journal/marinedrugs. Mar. Drugs 2019, 17, 121 synapses and neurons in the brain, representing the greatest of health challenges [1]. It is projected that more than 100 million people may be affected by AD by 2050 [2]. No effective drug is currently available to cure or prevent this disease. Given the huge socioeconomic burden associated with AD on global healthcare and medical systems, there is an urgent need for the development of new drugs to treat and/or prevent AD [3]
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