title: Tabersonine inhibits amyloid fibril formation and cytotoxicity of Aβ(1-42).
abstract: The misfolding and aggregation of amyloid beta (Aβ) peptides into amyloid fibrils are key events in the amyloid cascade hypothesis for the etiology of Alzheimer's disease (AD). Using thioflavin-T (ThT) fluorescence assay, atomic force microscopy, circular dichroism, size exclusion chromatography, surface plasmon resonance (SPR), and cytotoxicity tests, we demonstrate that tabersonine, an ingredient extracted from the bean of Voacanga africana, disrupts Aβ(1-42) aggregation and ameliorates Aβ aggregate-induced cytotoxicity. A small amount of tabersonine (e.g., 10 μM) can effectively inhibit the formation of Aβ(1-42) (e.g., 80 μM) fibrils or convert mature fibrils into largely innocuous amorphous aggregates. SPR results indicate that tabersonine binds to Aβ(1-42) oligomers in a dose-dependent way. Molecular dynamics (MD) simulations further confirm that tabersonine can bind to oligomers such as the pentamer of Aβ(1-42). Tabersonine preferentially interact with the β-sheet grooves of Aβ(1-42) containing aromatic and hydrophobic residues. The various binding sites and modes explain the diverse inhibitory effects of tabersonine on Aβ aggregation. Given that tabersonine is a natural product and a precursor for vincristine used in cancer chemotherapy, the biocompatibility and small size essential for permeating the blood-brain barrier make it a potential therapeutic drug candidate for treating AD.
authors: †College of Chemistry and Chemical Engineering, Central South University, Changsha, Hunan 410083, P. R. China.
authors: Tianhan
authors: T
authors: Kai
authors: †College of Chemistry and Chemical Engineering, Central South University, Changsha, Hunan 410083, P. R. China.
authors: Lin
authors: L
authors: Zhang
authors: ‡Department of Chemistry and Biochemistry, California State University, Los Angeles, Los Angeles, California 90032, United States.
authors: Xiaoying
authors: X
authors: Wang
authors: ‡Department of Chemistry and Biochemistry, California State University, Los Angeles, Los Angeles, California 90032, United States.|§College of Medical Technology and Engineering, Henan University of Science and Technology, Luoyang, Henan 471003, P. R. China.
authors: Aihua
authors: A
authors: Jing
authors: ‡Department of Chemistry and Biochemistry, California State University, Los Angeles, Los Angeles, California 90032, United States.
authors: Bingqing
authors: B
authors: Zhao
authors: ∥Department of Chemical and Biomolecular Engineering, The University of Akron, Akron, Ohio 44325, United States.
authors: Xiang
authors: X
authors: Yu
authors: ∥Department of Chemical and Biomolecular Engineering, The University of Akron, Akron, Ohio 44325, United States.
authors: Jie
authors: J
authors: Zheng
authors: ‡Department of Chemistry and Biochemistry, California State University, Los Angeles, Los Angeles, California 90032, United States.
authors: Feimeng
authors: F
authors: Zhou
mesh_terms: D000682:Amyloid / Q000187:drug effects* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D045744:Cell Line, Tumor; D002850:Chromatography, Gel; D002942:Circular Dichroism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D026121:Indole Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D018625:Microscopy, Atomic Force; D056004:Molecular Dynamics Simulation; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D010446:Peptide Fragments / Q000633:toxicity*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D020349:Surface Plasmon Resonance
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D026121:Indole Alkaloids; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011804:Quinolines; C075222:amyloid beta-protein (1-42); C009373:tabersonine
keywords: Alzheimer’s disease; Aβ(1−42) fibrillation; Tabersonine; aggregation; cytotoxicity; disaggregation