Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Research Article

A traditional Chinese Medicine, YXQN, Reduces Amyloid-induced Cytotoxicity by Inhibiting Aβ42 Aggregation and Fibril Formation

Author(s): Lichun Wang, Sitong Liu, Jiaqi Xu, Nobumoto Watanabe, Jun Di*, Wei Wei, Kevin H. Mayo, Jiang Li* and Xiaomeng Li*

Volume 26, Issue 7, 2020

Page: [780 - 789] Pages: 10

DOI: 10.2174/1381612826666200207120602

Price: $65

Abstract

Introduction: The accumulation of amyloid-β peptide (Aβ) decreases cerebral blood flow in elderly people with Alzheimer’s disease (AD) and is believed to be the initiator of this disorder. As a traditional Chinese medicine, Yangxue Qingnao (YXQN) improves cerebral insufficiency and attenuates cognitive impairment, showing potential against AD. But whether YXQN has the ability to block Aβ self-aggregation is rarely reported.

Objective: Here, we investigate the effects of YXQN on Aβ accumulation and its mediated cytotoxicity using a range of biochemical, biophysical, and cell-based approaches.

Methods: Thioflavin T assay, transmission electron microscope, and 1H NMR experiments were used to investigate the effects of YXQN on Aβ fibrogenesis and aggregation. Far-UV CD spectra were acquired to assess the alteration of YXQN on the conformation of the amyloid protein. Three short Aβ42 peptides (AA 1-16, AA 17-33 and AA 28-42) were designed to analyse the Aβ42 epitope to which YXQN components bind. The effect of YXQN on Aβ-induced cytotoxicity was investigated through SH-SY5Y cell viability assay.

Results: We provide evidence showing that YXQN clearly reduces Aβ42 fibrillogenesis and alters its β-sheet conformation, indicating the inhibition of primary nucleation of amyloid protein. Using the different Aβ short peptides, residues 17-33 were identified as the target epitope for YXNQ components interacting with Aβ42. Furthermore, in the SH-SY5Y cell injury model, our data show that high-dose YXQN attenuates amyloid-induced cytotoxicity approximately 60% and effectively ameliorates cell distortion in morphology.

Conclusion: Based on these results, YXQN exerts a neuroprotective effect by inhibiting Aβ42 toxic aggregation, which has the potential to combat AD.

Keywords: Aβ42 aggregation, YXQN, Aβ-induced cytotoxicity, Alzheimer's disease, fibrogenesis, aggregation.

[1]
2018 Alzheimer’s disease facts and figures. Alzheimers Dement 2018; 14(3): 367-429.
[http://dx.doi.org/10.1016/j.jalz.2018.02.001]
[2]
Zhang Y, Lu L, Jia J, et al. A lifespan observation of a novel mouse model: in vivo evidence supports aβ oligomer hypothesis. PLoS One 2014; 9(1) e85885
[http://dx.doi.org/10.1371/journal.pone.0085885] [PMID: 24465766]
[3]
Mucke L, Selkoe DJ. Neurotoxicity of amyloid β-protein: synaptic and network dysfunction. Cold Spring Harb Perspect Med 2012; 2(7) a006338
[http://dx.doi.org/10.1101/cshperspect.a006338] [PMID: 22762015]
[4]
Tomiyama T, Matsuyama S, Iso H, et al. A mouse model of amyloid beta oligomers: their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo. J Neurosci 2010; 30(14): 4845-56.
[http://dx.doi.org/10.1523/JNEUROSCI.5825-09.2010] [PMID: 20371804]
[5]
Walsh DM, Klyubin I, Fadeeva JV, et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 2002; 416(6880): 535-9.
[http://dx.doi.org/10.1038/416535a] [PMID: 11932745]
[6]
Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7(3): 280-92.
[http://dx.doi.org/10.1016/j.jalz.2011.03.003] [PMID: 21514248]
[7]
Smith DP, Radford SE, Ashcroft AE. Elongated oligomers in beta2-microglobulin amyloid assembly revealed by ion mobility spectrometry-mass spectrometry. Proc Natl Acad Sci USA 2010; 107(15): 6794-8.
[http://dx.doi.org/10.1073/pnas.0913046107] [PMID: 20351246]
[8]
Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science 1992; 256(5054): 184-5.
[http://dx.doi.org/10.1126/science.1566067] [PMID: 1566067]
[9]
Habchi J, Arosio P, Perni M, et al. An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Aβ42 aggregates linked with Alzheimer’s disease. Sci Adv 2016; 2(2) e1501244
[http://dx.doi.org/10.1126/sciadv.1501244] [PMID: 26933687]
[10]
Bieschke J. Natural compounds may open new routes to treatment of amyloid diseases. Neurotherapeutics 2013; 10(3): 429-39.
[http://dx.doi.org/10.1007/s13311-013-0192-7] [PMID: 23670234]
[11]
Chen J, Armstrong AH, Koehler AN, Hecht MH. Small molecule microarrays enable the discovery of compounds that bind the Alzheimer’s Aβ peptide and reduce its cytotoxicity. J Am Chem Soc 2010; 132(47): 17015-22.
[http://dx.doi.org/10.1021/ja107552s] [PMID: 21062056]
[12]
Razzaghi-Asl N, Karimi A, Ebadi A. The potential of natural product vs neurodegenerative disorders: In silico study of artoflavanocoumarin as BACE-1 inhibitor. Comput Biol Chem 2018; 77: 307-17.
[http://dx.doi.org/10.1016/j.compbiolchem.2018.10.015] [PMID: 30445338]
[13]
Jiang L, Liu C, Leibly D, et al. Structure-based discovery of fiber-binding compounds that reduce the cytotoxicity of amyloid beta. eLife 2013; 2 e00857
[http://dx.doi.org/10.7554/eLife.00857] [PMID: 23878726]
[14]
Ruderisch N, Schlatter D, Kuglstatter A, et al. Potent and selective BACE-1 peptide inhibitors lower brain Aβ levels mediated by brain shuttle transport. EBioMedicine 2017; 24: 76-92.
[http://dx.doi.org/10.1016/j.ebiom.2017.09.004] [PMID: 28923680]
[15]
Morgado I, Wieligmann K, Bereza M, et al. Molecular basis of β-amyloid oligomer recognition with a conformational antibody fragment. Proc Natl Acad Sci USA 2012; 109(31): 12503-8.
[http://dx.doi.org/10.1073/pnas.1206433109] [PMID: 22814377]
[16]
Liu T, Bitan G. Modulating self-assembly of amyloidogenic proteins as a therapeutic approach for neurodegenerative diseases: strategies and mechanisms. ChemMedChem 2012; 7(3): 359-74.
[http://dx.doi.org/10.1002/cmdc.201100585] [PMID: 22323134]
[17]
Atwal JK, Chen Y, Chiu C, et al. A therapeutic antibody targeting BACE1 inhibits amyloid-β production in vivo. Sci Transl Med 2011; 3(84) 84ra43
[http://dx.doi.org/10.1126/scitranslmed.3002254] [PMID: 21613622]
[18]
Meakin PJ, Mezzapesa A, Benabou E, et al. The beta secretase BACE1 regulates the expression of insulin receptor in the liver. Nat Commun 2018; 9(1): 1306.
[http://dx.doi.org/10.1038/s41467-018-03755-2] [PMID: 29610518]
[19]
Klaver DW, Wilce MC, Cui H, et al. Is BACE1 a suitable therapeutic target for the treatment of Alzheimer’s disease? Current strategies and future directions. Biol Chem 2010; 391(8): 849-59.
[http://dx.doi.org/10.1515/bc.2010.089] [PMID: 20731541]
[20]
Yang F, Lim GP, Begum AN, et al. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem 2005; 280(7): 5892-901.
[http://dx.doi.org/10.1074/jbc.M404751200] [PMID: 15590663]
[21]
Park SY, Kim DS. Discovery of natural products from Curcuma longa that protect cells from beta-amyloid insult: a drug discovery effort against Alzheimer’s disease. J Nat Prod 2002; 65(9): 1227-31.
[http://dx.doi.org/10.1021/np010039x] [PMID: 12350137]
[22]
Karran E, Hardy J. A critique of the drug discovery and phase 3 clinical programs targeting the amyloid hypothesis for Alzheimer disease. Ann Neurol 2014; 76(2): 185-205.
[http://dx.doi.org/10.1002/ana.24188] [PMID: 24853080]
[23]
Kokjohn TA, Roher AE. Antibody responses, amyloid-beta peptide remnants and clinical effects of AN-1792 immunization in patients with AD in an interrupted trial. CNS Neurol Disord Drug Targets 2009; 8(2): 88-97.
[http://dx.doi.org/10.2174/187152709787847315] [PMID: 19355930]
[24]
Iturria-Medina Y, Sotero RC, Toussaint PJ, Mateos-Pérez JM, Evans AC. Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis. Nat Commun 2016; 7: 11934.
[http://dx.doi.org/10.1038/ncomms11934] [PMID: 27327500]
[25]
Nortley R, Korte N, Izquierdo P, et al. Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes. Science 2019; 365(6450): 365.
[http://dx.doi.org/10.1126/science.aav9518] [PMID: 31221773]
[26]
Gould IG, Tsai P, Kleinfeld D, Linninger A. The capillary bed offers the largest hemodynamic resistance to the cortical blood supply. J Cereb Blood Flow Metab 2017; 37(1): 52-68.
[http://dx.doi.org/10.1177/0271678X16671146] [PMID: 27780904]
[27]
Zhang X, Zhou K, Wang R, et al. Hypoxia-inducible factor 1alpha (HIF-1alpha)-mediated hypoxia increases BACE1 expression and beta-amyloid generation. J Biol Chem 2007; 282(15): 10873-80.
[http://dx.doi.org/10.1074/jbc.M608856200] [PMID: 17303576]
[28]
Sun X, He G, Qing H, et al. Hypoxia facilitates Alzheimer’s disease pathogenesis by up-regulating BACE1 gene expression. Proc Natl Acad Sci USA 2006; 103(49): 18727-32.
[http://dx.doi.org/10.1073/pnas.0606298103] [PMID: 17121991]
[29]
Xiong L, Zhang JJ, Sun D, Liu H. Therapeutic benefit of Yangxue Qingnao Granule on cognitive impairment induced by chronic cerebral hypoperfusion in rats. Chin J Integr Med 2011; 17(2): 134-40.
[http://dx.doi.org/10.1007/s11655-011-0643-0] [PMID: 21390580]
[30]
Gu XX, Cai DF, Yang YK, Teng Y, Chen YP, Wen M. Study on Yangxue Qingnao granule in treating chronic cerebrovascular insufficiency. Chin J Integr Med 2005; 11(1): 22-6.
[http://dx.doi.org/10.1007/BF02835743] [PMID: 15975302]
[31]
Feng JL, Zeng AY, Du YP. Effect of yangxue qingnao granule on microcirculation and cerebral blood flow in patients with migraine. Zhongguo Zhong Xi Yi Jie He Za Zhi 2004; 24(4): 357-8.
[PMID: 15143727]
[32]
Wu C, Liao L, Yan X, et al. Effects of Yangxue Qingnao granules on chronic cerebral circulation insufficiency: a randomized, double-blind, double-dummy, controlled multicentre trial. Psychogeriatrics 2013; 13(1): 29-34.
[http://dx.doi.org/10.1111/j.1479-8301.2012.00423.x] [PMID: 23551409]
[33]
Wang X, Song R, Lu W, et al. YXQN Reduces Alzheimer’s disease-like pathology and cognitive decline in APPswePS1dE9 transgenic mice. Front Aging Neurosci 2017; 9: 157.
[http://dx.doi.org/10.3389/fnagi.2017.00157] [PMID: 28603494]
[34]
LeVine H III. Thioflavine T interaction with synthetic Alzheimer’s disease beta-amyloid peptides: detection of amyloid aggregation in solution. Protein Sci 1993; 2(3): 404-10.
[http://dx.doi.org/10.1002/pro.5560020312] [PMID: 8453378]
[35]
Dammers C, Schwarten M, Buell AK, Willbold D. Pyroglutamate-modified Aβ(3-42) affects aggregation kinetics of Aβ(1-42) by accelerating primary and secondary pathways. Chem Sci (Camb) 2017; 8(7): 4996-5004.
[http://dx.doi.org/10.1039/C6SC04797A] [PMID: 28970886]
[36]
Korshavn KJ, Satriano C, Lin Y, et al. Reduced lipid bilayer thickness regulates the aggregation and cytotoxicity of amyloid-β. J Biol Chem 2017; 292(11): 4638-50.
[http://dx.doi.org/10.1074/jbc.M116.764092] [PMID: 28154182]
[37]
Bansal S, Maurya IK, Yadav N, et al. C-Terminal fragment, Aβ32-37, analogues protect against aβ aggregation-induced toxicity. ACS Chem Neurosci 2016; 7(5): 615-23.
[http://dx.doi.org/10.1021/acschemneuro.6b00006] [PMID: 26835536]
[38]
Wang M, Jiji RD. Spectroscopic detection of β -sheet structure in nascent Aβ oligomers. J Biophotonics 2011; 4(9): 637-44.
[http://dx.doi.org/10.1002/jbio.201100023] [PMID: 21702084]
[39]
Lührs T, Ritter C, Adrian M, et al. 3D structure of Alzheimer’s amyloid-beta(1-42) fibrils. Proc Natl Acad Sci USA 2005; 102(48): 17342-7.
[http://dx.doi.org/10.1073/pnas.0506723102] [PMID: 16293696]
[40]
Cobb NJ, Sönnichsen FD, McHaourab H, Surewicz WK. Molecular architecture of human prion protein amyloid: a parallel, in-register beta-structure. Proc Natl Acad Sci USA 2007; 104(48): 18946-51.
[http://dx.doi.org/10.1073/pnas.0706522104] [PMID: 18025469]
[41]
Luca S, Yau WM, Leapman R, Tycko R. Peptide conformation and supramolecular organization in amylin fibrils: constraints from solid-state NMR. Biochemistry 2007; 46(47): 13505-22.
[http://dx.doi.org/10.1021/bi701427q] [PMID: 17979302]
[42]
Petkova AT, Leapman RD, Guo Z, Yau WM, Mattson MP, Tycko R. Self-propagating, molecular-level polymorphism in Alzheimer’s beta-amyloid fibrils. Science 2005; 307(5707): 262-5.
[http://dx.doi.org/10.1126/science.1105850] [PMID: 15653506]
[43]
Habchi J, Chia S, Limbocker R, et al. Systematic development of small molecules to inhibit specific microscopic steps of Aβ42 aggregation in Alzheimer’s disease. Proc Natl Acad Sci USA 2017; 114(2): E200-8.
[http://dx.doi.org/10.1073/pnas.1615613114] [PMID: 28011763]
[44]
Du WJ, Guo JJ, Gao MT, et al. Brazilin inhibits amyloid β-protein fibrillogenesis, remodels amyloid fibrils and reduces amyloid cytotoxicity. Sci Rep 2015; 5: 7992.
[http://dx.doi.org/10.1038/srep07992] [PMID: 25613018]
[45]
Miners JS, Barua N, Kehoe PG, Gill S, Love S. Aβ-degrading enzymes: potential for treatment of Alzheimer disease. J Neuropathol Exp Neurol 2011; 70(11): 944-59.
[http://dx.doi.org/10.1097/NEN.0b013e3182345e46] [PMID: 22002425]
[46]
Pizzi A, Dichiarante V, Terraneo G, Metrangolo P. Crystallographic insights into the self-assembly of KLVFF amyloid-beta peptides. Biopolymers 2017. In press
[PMID: 29178159]
[47]
Qu A, Huang F, Li A, et al. The synergistic effect between KLVFF and self-assembly chaperones on both disaggregation of beta-amyloid fibrils and reducing consequent toxicity. Chem Commun (Camb) 2017; 53(7): 1289-92.
[http://dx.doi.org/10.1039/C6CC07803F] [PMID: 28067349]
[48]
Arai T, Sasaki D, Araya T, Sato T, Sohma Y, Kanai M. A cyclic KLVFF-derived peptide aggregation inhibitor induces the formation of less-toxic off-pathway amyloid-β oligomers. ChemBioChem 2014; 15(17): 2577-83.
[http://dx.doi.org/10.1002/cbic.201402430] [PMID: 25262917]
[49]
D’Ursi AM, Armenante MR, Guerrini R, Salvadori S, Sorrentino G, Picone D. Solution structure of amyloid beta-peptide (25-35) in different media. J Med Chem 2004; 47(17): 4231-8.
[http://dx.doi.org/10.1021/jm040773o] [PMID: 15293994]
[50]
Kohno T, Kobayashi K, Maeda T, Sato K, Takashima A. Three-dimensional structures of the amyloid beta peptide (25-35) in membrane-mimicking environment. Biochemistry 1996; 35(50): 16094-104.
[http://dx.doi.org/10.1021/bi961598j] [PMID: 8973180]
[51]
Wang K, Zhu L, Zhu X, et al. Protective effect of paeoniflorin on Aβ25-35-induced SH-SY5Y cell injury by preventing mitochondrial dysfunction. Cell Mol Neurobiol 2014; 34(2): 227-34.
[http://dx.doi.org/10.1007/s10571-013-0006-9] [PMID: 24263411]
[52]
Fan S, Zhang B, Luan P, et al. PI3K/AKT/mTOR/p70S6K pathway is involved in Aβ25-35-induced autophagy. BioMed Res Int 2015; 2015 161020
[http://dx.doi.org/10.1155/2015/161020] [PMID: 26583091]
[53]
Diaz A, Limon D, Chávez R, Zenteno E, Guevara J. Aβ25-35 injection into the temporal cortex induces chronic inflammation that contributes to neurodegeneration and spatial memory impairment in rats. J Alzheimers Dis 2012; 30(3): 505-22.
[http://dx.doi.org/10.3233/JAD-2012-111979] [PMID: 22430532]
[54]
Liu YC, Gao XX, Chen L, You XQ. Rapamycin suppresses Aβ25-35- or LPS-induced neuronal inflammation via modulation of NF-κB signaling. Neuroscience 2017; 355: 188-99.
[http://dx.doi.org/10.1016/j.neuroscience.2017.05.005] [PMID: 28504198]
[55]
Huang M, Liang Y, Liu Q, Chang X, Guo Y. WITHDRAWN: berberine attenuates Aβ25-35-induced apoptosis in primary cultured hippocampal neurons. Biochem Biophys Res Commun 2016. In press
[http://dx.doi.org/10.1016/j.bbrc.2016.12.166] [PMID: 28034755]
[56]
Arai T, Araya T, Sasaki D, et al. Rational design and identification of a non-peptidic aggregation inhibitor of amyloid-β based on a pharmacophore motif obtained from cyclo[-Lys-Leu-Val-Phe-Phe-]. Angew Chem Int Ed Engl 2014; 53(31): 8236-9.
[http://dx.doi.org/10.1002/anie.201405109] [PMID: 24931598]
[57]
Warmack RA, Boyer DR, Zee CT, et al. Structure of amyloid-β (20-34) with Alzheimer’s-associated isomerization at Asp23 reveals a distinct protofilament interface. Nat Commun 2019; 10(1): 3357.
[http://dx.doi.org/10.1038/s41467-019-11183-z] [PMID: 31350392]
[58]
Krotee P, Griner SL, Sawaya MR, et al. Common fibrillar spines of amyloid-β and human islet amyloid polypeptide revealed by microelectron diffraction and structure-based inhibitors. J Biol Chem 2018; 293(8): 2888-902.
[http://dx.doi.org/10.1074/jbc.M117.806109] [PMID: 29282295]
[59]
Yang DL, Tong L, Li XW, Li DX, Liu WY. [Identification of chemical constituents in Yangxue Qingnao granule by UPLC-Q-TOF/MS~E]. Yao Xue Xue Bao 2016; 51(5): 797-805.
[PMID: 29878728]
[60]
Ali MY, Jannat S, Edraki N, et al. Flavanone glycosides inhibit β-site amyloid precursor protein cleaving enzyme 1 and cholinesterase and reduce Aβ aggregation in the amyloidogenic pathway. Chem Biol Interact 2019; 309 108707
[http://dx.doi.org/10.1016/j.cbi.2019.06.020] [PMID: 31194956]
[61]
Wang YX, Ren Q, Yan ZY, et al. Flavonoids and their derivatives with β-amyloid aggregation inhibitory activity from the leaves and twigs of Pithecellobium clypearia Benth. Bioorg Med Chem Lett 2017; 27(21): 4823-7.
[http://dx.doi.org/10.1016/j.bmcl.2017.09.051] [PMID: 28988761]
[62]
Marsh DT, Das S, Ridell J, Smid SD. Structure-activity relationships for flavone interactions with amyloid β reveal a novel anti-aggregatory and neuroprotective effect of 2′,3′,4′-trihydroxyflavone (2-D08). Bioorg Med Chem 2017; 25(14): 3827-34.
[http://dx.doi.org/10.1016/j.bmc.2017.05.041] [PMID: 28559058]
[63]
DeToma AS, Krishnamoorthy J, Nam Y, et al. Synthetic flavonoids, aminoisoflavones: interaction and reactivity with metal-free and metal-associated amyloid-β species. Chem Sci (Camb) 2014; 5(12): 4851-62.
[http://dx.doi.org/10.1039/C4SC01531B] [PMID: 25383163]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy