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9-Methylfascaplysin Is a More Potent Aβ Aggregation Inhibitor than the Marine-Derived Alkaloid, Fascaplysin, and Produces Nanomolar Neuroprotective Effects in SH-SY5Y Cells

1
Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo 315211, China
2
Li Dak Sum Yip Yio Chin Kenneth Li Marine Biopharmaceutical Research Center, College of Food and Pharmaceutical Sciences, Ningbo University, Ningbo 315211, China
3
Key Laboratory of Industrial Fermentation Microbiology of Education, State Key Laboratory of Food Nutrition and Safety, College of Biotechnology, Tianjin University of Science & Technology, Tianjin 300457, China
4
School of Materials Science and Chemical Engineering, Ningbo University, Ningbo 315211, China
*
Authors to whom correspondence should be addressed.
These authors contribute equally.
Mar. Drugs 2019, 17(2), 121; https://doi.org/10.3390/md17020121
Received: 11 January 2019 / Revised: 2 February 2019 / Accepted: 7 February 2019 / Published: 18 February 2019
(This article belongs to the Special Issue Bioactive Compounds from Marine Sponges)
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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. View Full-Text
Keywords: fascaplysin; Alzheimer’s disease; Aβ; oligomer; β-carboline fascaplysin; Alzheimer’s disease; ; oligomer; β-carboline
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Sun, Q.; Liu, F.; Sang, J.; Lin, M.; Ma, J.; Xiao, X.; Yan, S.; Naman, C.B.; Wang, N.; He, S.; Yan, X.; Cui, W.; Liang, H. 9-Methylfascaplysin Is a More Potent Aβ Aggregation Inhibitor than the Marine-Derived Alkaloid, Fascaplysin, and Produces Nanomolar Neuroprotective Effects in SH-SY5Y Cells. Mar. Drugs 2019, 17, 121.

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