Keampferol-3-O-rhamnoside abrogates amyloid beta toxicity by modulating monomers and remodeling oligomers and fibrils to non-toxic aggregates

Journal of Biomedical Science

Il-Seon Park¹  Song Yub Shin¹  Eun-Rhan Woo⁵  Vijay Sankar Ramasamy³  Mohammad Shahnawaz⁶  Arjun Thapa⁴  Md Golam Sharoar² 

[1] Department of Cellular and Molecular Medicine, Chosun University, Gwanju, 501-759, Republic of Korea;Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi, 6205, Bangladesh;Department of Bio-materials Engineering, Chosun University, Gwanju, 501-759, Republic of Korea;Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA;College of Pharmacy, Chosun University, Gwanju, 501-759, Republic of Korea;Medical School, The University of Texas Health Science Center at Houston, 6431 Fannin St, Houston, TX, 77030, USA

关键词: Alzheimer’s disease;    Cytotoxicity;    Aggregation;    Oligomer;    Kaempferol-3-O-rhamnoside;    Aβ;   

Others  :  824364
DOI  :  10.1186/1423-0127-19-104

 received in 2012-10-22, accepted in 2012-12-20,  发布年份 2012

【 摘 要 】

Background

Aggregation of soluble, monomeric β- amyloid (Aβ) to oligomeric and then insoluble fibrillar Aβ is a key pathogenic feature in development of Alzheimer’s disease (AD). Increasing evidence suggests that toxicity is linked to diffusible Aβ oligomers, rather than to insoluble fibrils. The use of naturally occurring small molecules for inhibition of Aβ aggregation has recently attracted significant interest for development of effective therapeutic strategies against the disease. A natural polyphenolic flavone, Kaempferol-3-O-rhamnoside (K-3-rh), was utilized to investigate its effects on aggregation and cytotoxic effects of Aβ42 peptide. Several biochemical techniques were used to determine the conformational changes and cytotoxic effect of the peptide in the presence and absence of K-3-rh.

Results

K-3-rh showed a dose-dependent effect against Aβ42 mediated cytotoxicity. Anti-amyloidogenic properties of K-3-rh were found to be efficient in inhibiting fibrilogenesis and secondary structural transformation of the peptide. The consequence of these inhibitions was the accumulation of oligomeric structural species. The accumulated aggregates were smaller, soluble, non-β-sheet and non-toxic aggregates, compared to preformed toxic Aβ oligomers. K-3-rh was also found to have the remodeling properties of preformed soluble oligomers and fibrils. Both of these conformers were found to remodel into non-toxic aggregates. The results showed that K-3-rh interacts with different Aβ conformers, which affects fibril formation, oligomeric maturation and fibrillar stabilization.

Conclusion

K-3-rh is an efficient molecule to hinder the self assembly and to abrogate the cytotoxic effects of Aβ42 peptide. Hence, K-3-rh and small molecules with similar structure might be considered for therapeutic development against AD.

【 授权许可】

   
2012 Sharoar et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Selkoe DJ: Alzheimer disease: mechanistic understanding predicts novel therapies. Ann Intern Med 2004, 140(8):627-638.
• [2]Hardy J, Selkoe DJ: The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002, 297(5580):353-356.
• [3]Haass C, Hung AY, Schlossmacher MG, Oltersdorf T, Teplow DB, Selkoe DJ: Normal cellular processing of the beta-amyloid precursor protein results in the secretion of the amyloid beta peptide and related molecules. Ann N Y Acad Sci 1993, 695:109-116.
• [4]Selkoe DJ: Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 2001, 81(2):741-766.
• [5]Jarrett JT, Berger EP, Lansbury PT Jr: The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer’s disease. Biochemistry 1993, 32(18):4693-4697.
• [6]Naiki H, Nakakuki K: First-order kinetic model of Alzheimer’s beta-amyloid fibril extension in vitro. Lab Invest 1996, 74(2):374-383.
• [7]Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, et al.: Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A 1998, 95(11):6448-6453.
• [8]Kayed R, Head E, Thompson JL, McIntire TM, Milton SC, Cotman CW, Glabe CG: Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 2003, 300(5618):486-489.
• [9]Nguyen HD, Hall CK: Molecular dynamics simulations of spontaneous fibril formation by random-coil peptides. Proc Natl Acad Sci U S A 2004, 101(46):16180-16185.
• [10]Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH: A specific amyloid-beta protein assembly in the brain impairs memory. Nature 2006, 440(7082):352-357.
• [11]Glabe CG: Conformation-dependent antibodies target diseases of protein misfolding. Trends Biochem Sci 2004, 29(10):542-547.
• [12]Haass C, Selkoe DJ: Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 2007, 8(2):101-112.
• [13]Frid P, Anisimov SV, Popovic N: Congo red and protein aggregation in neurodegenerative diseases. Brain Res Rev 2007, 53(1):135-160.
• [14]Begum AN, Jones MR, Lim GP, Morihara T, Kim P, Heath DD, Rock CL, Pruitt MA, Yang F, Hudspeth B, et al.: Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer’s disease. J Pharmacol Exp Ther 2008, 326(1):196-208.
• [15]Solomon B: Antibody-mediated immunotherapy for Alzheimer’s disease. Curr Opin Investig Drugs 2007, 8(7):519-524.
• [16]Soto C, Sigurdsson EM, Morelli L, Kumar RA, Castano EM, Frangione B: Beta-sheet breaker peptides inhibit fibrillogenesis in a rat brain model of amyloidosis: implications for Alzheimer’s therapy. Nat Med 1998, 4(7):822-826.
• [17]Soto P, Griffin MA, Shea JE: New insights into the mechanism of Alzheimer amyloid-beta fibrillogenesis inhibition by N-methylated peptides. Biophys J 2007, 93(9):3015-3025.
• [18]Yang DS, Yip CM, Huang TH, Chakrabartty A, Fraser PE: Manipulating the amyloid-beta aggregation pathway with chemical chaperones. J Biol Chem 1999, 274(46):32970-32974.
• [19]Necula M, Kayed R, Milton S, Glabe CG: Small molecule inhibitors of aggregation indicate that amyloid beta oligomerization and fibrillization pathways are independent and distinct. J Biol Chem 2007, 282(14):10311-10324.
• [20]Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, Chen PP, Kayed R, Glabe CG, Frautschy SA, et al.: Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem 2005, 280(7):5892-5901.
• [21]Pollack SJ, Sadler II, Hawtin SR, Tailor VJ, Shearman MS: Sulfonated dyes attenuate the toxic effects of beta-amyloid in a structure-specific fashion. Neurosci Lett 1995, 197(3):211-214.
• [22]Lee VM: Amyloid binding ligands as Alzheimer’s disease therapies. Neurobiol Aging 2002, 23(6):1039-1042.
• [23]Spencer JP: Flavonoids: modulators of brain function? Br J Nutr 2008, 99 E Suppl 1:ES60-ES77.
• [24]Bagchi D, Carryl OR, Tran MX, Bagchi M, Garg A, Milnes MM, Williams CB, Balmoori J, Bagchi DJ, Mitra S, et al.: Acute and chronic stress-induced oxidative gastrointestinal mucosal injury in rats and protection by bismuth subsalicylate. Mol Cell Biochem 1999, 196(1–2):109-116.
• [25]Yamamoto Y, Gaynor RB: Therapeutic potential of inhibition of the NF-kappaB pathway in the treatment of inflammation and cancer. J Clin Invest 2001, 107(2):135-142.
• [26]Cushnie TP, Lamb AJ: Antimicrobial activity of flavonoids. Int J Antimicrob Agents 2005, 26(5):343-356.
• [27]Commenges D, Scotet V, Renaud S, Jacqmin-Gadda H, Barberger-Gateau P, Dartigues JF: Intake of flavonoids and risk of dementia. Eur J Epidemiol 2000, 16(4):357-363.
• [28]Yao Z, Drieu K, Papadopoulos V: The Ginkgo biloba extract EGb 761 rescues the PC12 neuronal cells from beta-amyloid-induced cell death by inhibiting the formation of beta-amyloid-derived diffusible neurotoxic ligands. Brain Res 2001, 889(1–2):181-190.
• [29]Luo Y, Smith JV, Paramasivam V, Burdick A, Curry KJ, Buford JP, Khan I, Netzer WJ, Xu H, Butko P: Inhibition of amyloid-beta aggregation and caspase-3 activation by the Ginkgo biloba extract EGb761. Proc Natl Acad Sci U S A 2002, 99(19):12197-12202.
• [30]Ono K, Condron MM, Ho L, Wang J, Zhao W, Pasinetti GM, Teplow DB: Effects of grape seed-derived polyphenols on amyloid beta-protein self-assembly and cytotoxicity. J Biol Chem 2008, 283(47):32176-32187.
• [31]Rigacci S, Guidotti V, Bucciantini M, Nichino D, Relini A, Berti A, Stefani M: Abeta(1–42) aggregates into non-toxic amyloid assemblies in the presence of the natural polyphenol oleuropein aglycon. Curr Alzheimer Res 2011, 8(8):841-852.
• [32]Qin XY, Cheng Y, Yu LC: Potential protection of green tea polyphenols against intracellular amyloid beta-induced toxicity on primary cultured prefrontal cortical neurons of rats. Neurosci Lett 2012, 513(2):170-173.
• [33]Kim JK, Choi SJ, Cho HY, Hwang HJ, Kim YJ, Lim ST, Kim CJ, Kim HK, Peterson S, Shin DH: Protective effects of kaempferol (3,4′,5,7-tetrahydroxyflavone) against amyloid beta peptide (Abeta)-induced neurotoxicity in ICR mice. Biosci Biotechnol Biochem 2010, 74(2):397-401.
• [34]Lu JH, Ardah MT, Durairajan SS, Liu LF, Xie LX, Fong WF, Hasan MY, Huang JD, El-Agnaf OM, Li M: Baicalein Inhibits Formation of alpha-Synuclein Oligomers within Living Cells and Prevents Abeta Peptide Fibrillation and Oligomerisation. Chembiochem 2011, 12(4):615-624.
• [35]Feng Y, Wang XP, Yang SG, Wang YJ, Zhang X, Du XT, Sun XX, Zhao M, Huang L, Liu RT: Resveratrol inhibits beta-amyloid oligomeric cytotoxicity but does not prevent oligomer formation. Neurotoxicology 2009, 30(6):986-995.
• [36]Ramassamy C: Emerging role of polyphenolic compounds in the treatment of neurodegenerative diseases: a review of their intracellular targets. Eur J Pharmacol 2006, 545(1):51-64.
• [37]Lee CW, Choi HJ, Kim HS, Kim DH, Chang IS, Moon HT, Lee SY, Oh WK, Woo ER: Biflavonoids isolated from Selaginella tamariscina regulate the expression of matrix metalloproteinase in human skin fibroblasts. Bioorg Med Chem 2008, 16(2):732-738.
• [38]Shahnawaz M, Thapa A, Park IS: Stable activity of a deubiquitylating enzyme (Usp2-cc) in the presence of high concentrations of urea and its application to purify aggregation-prone peptides. Biochem Biophys Res Commun 2007, 359(3):801-805.
• [39]Thapa A, Woo ER, Chi EY, Sharoar MG, Jin HG, Shin SY, Park IS: Biflavonoids Are Superior to Monoflavonoids in Inhibiting Amyloid-beta Toxicity and Fibrillogenesis via Accumulation of Nontoxic Oligomer-like Structures. Biochemistry 2011, 50(13):2445-2455.
• [40]Naiki H, Hasegawa K, Yamaguchi I, Nakamura H, Gejyo F, Nakakuki K: Apolipoprotein E and antioxidants have different mechanisms of inhibiting Alzheimer’s beta-amyloid fibril formation in vitro. Biochemistry 1998, 37(51):17882-17889.
• [41]Kirkitadze MD, Condron MM, Teplow DB: Identification and characterization of key kinetic intermediates in amyloid beta-protein fibrillogenesis. J Mol Biol 2001, 312(5):1103-1119.
• [42]Moss MA, Varvel NH, Nichols MR, Reed DK, Rosenberry TL: Nordihydroguaiaretic acid does not disaggregate beta-amyloid(1–40) protofibrils but does inhibit growth arising from direct protofibril association. Mol Pharmacol 2004, 66(3):592-600.
• [43]Zou K, Gong JS, Yanagisawa K, Michikawa M: A novel function of monomeric amyloid beta-protein serving as an antioxidant molecule against metal-induced oxidative damage. J Neurosci 2002, 22(12):4833-4841.
• [44]Ono K, Yoshiike Y, Takashima A, Hasegawa K, Naiki H, Yamada M: Potent anti-amyloidogenic and fibril-destabilizing effects of polyphenols in vitro: implications for the prevention and therapeutics of Alzheimer’s disease. J Neurochem 2003, 87(1):172-181.
• [45]Masuda M, Suzuki N, Taniguchi S, Oikawa T, Nonaka T, Iwatsubo T, Hisanaga S, Goedert M, Hasegawa M: Small molecule inhibitors of alpha-synuclein filament assembly. Biochemistry 2006, 45(19):6085-6094.
• [46]Chromy BA, Nowak RJ, Lambert MP, Viola KL, Chang L, Velasco PT, Jones BW, Fernandez SJ, Lacor PN, Horowitz P, et al.: Self-assembly of Abeta(1–42) into globular neurotoxins. Biochemistry 2003, 42(44):12749-12760.
• [47]Walsh DM, Hartley DM, Kusumoto Y, Fezoui Y, Condron MM, Lomakin A, Benedek GB, Selkoe DJ, Teplow DB: Amyloid beta-protein fibrillogenesis. Structure and biological activity of protofibrillar intermediates. J Biol Chem 1999, 274(36):25945-25952.
• [48]McLean CA, Cherny RA, Fraser FW, Fuller SJ, Smith MJ, Beyreuther K, Bush AI, Masters CL: Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann Neurol 1999, 46(6):860-866.
• [49]Tomic JL, Pensalfini A, Head E, Glabe CG: Soluble fibrillar oligomer levels are elevated in Alzheimer’s disease brain and correlate with cognitive dysfunction. Neurobiol Dis 2009, 35(3):352-358.
• [50]Ladiwala AR, Lin JC, Bale SS, Marcelino-Cruz AM, Bhattacharya M, Dordick JS, Tessier PM: Resveratrol selectively remodels soluble oligomers and fibrils of amyloid Abeta into off-pathway conformers. J Biol Chem 2010, 285(31):24228-24237.
• [51]Ladiwala AR, Mora-Pale M, Lin JC, Bale SS, Fishman ZS, Dordick JS, Tessier PM: Polyphenolic glycosides and aglycones utilize opposing pathways to selectively remodel and inactivate toxic oligomers of amyloid beta. Chembiochem 2011, 12(11):1749-1758.
• [52]Zhu JT, Choi RC, Chu GK, Cheung AW, Gao QT, Li J, Jiang ZY, Dong TT, Tsim KW: Flavonoids possess neuroprotective effects on cultured pheochromocytoma PC12 cells: a comparison of different flavonoids in activating estrogenic effect and in preventing beta-amyloid-induced cell death. J Agric Food Chem 2007, 55(6):2438-2445.
• [53]Porat Y, Mazor Y, Efrat S, Gazit E: Inhibition of islet amyloid polypeptide fibril formation: a potential role for heteroaromatic interactions. Biochemistry 2004, 43(45):14454-14462.
• [54]Nakagami Y, Nishimura S, Murasugi T, Kaneko I, Meguro M, Marumoto S, Kogen H, Koyama K, Oda T: A novel beta-sheet breaker, RS-0406, reverses amyloid beta-induced cytotoxicity and impairment of long-term potentiation in vitro. Br J Pharmacol 2002, 137(5):676-682.
• [55]Porat Y, Abramowitz A, Gazit E: Inhibition of amyloid fibril formation by polyphenols: structural similarity and aromatic interactions as a common inhibition mechanism. Chem Biol Drug Des 2006, 67(1):27-37.
• [56]Ladiwala AR, Dordick JS, Tessier PM: Aromatic small molecules remodel toxic soluble oligomers of amyloid beta through three independent pathways. J Biol Chem 2011, 286(5):3209-3218.
• [57]Ladiwala AR, Perchiacca JM, Fishman ZS, Bhattacharya M, Hickey AM, Domigan BG, Dordick JS, Tessier PM: Polyphenolic disaccharides endow proteins with unusual resistance to aggregation. Biotechnol Bioeng 2012, 109(7):1869-1874.