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Polyphenols as Therapeutic Molecules in Alzheimer’s Disease Through Modulating Amyloid Pathways

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Abstract

Alzheimer’s disease (AD) is a complex and multifactorial neurodegenerative condition. The complex pathology of this disease includes oxidative stress, metal deposition, formation of aggregates of amyloid and tau, enhanced immune responses, and disturbances in cholinesterase. Drugs targeted toward reduction of amyloidal load have been discovered, but there is no effective pharmacological treatment for combating the disease so far. Natural products have become an important avenue for drug discovery research. Polyphenols are natural products that have been shown to be effective in the modulation of the type of neurodegenerative changes seen in AD, suggesting a possible therapeutic role. The present review focuses on the chemistry of polyphenols and their role in modulating amyloid precursor protein (APP) processing. We also provide new hypotheses on how these therapeutic molecules may modulate APP processing, prevent Aβ aggregation, and favor disruption of preformed fibrils. Finally, the role of polyphenols in modulating Alzheimer’s pathology is discussed.

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Reference

  1. Hashimoto M, Rockenstein E, Crews L, Masliah E (2003) Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer’s and Parkinson’s diseases. Neuromolecular Med 4:21–36. doi:10.1385/NMM:4:1-2:21

  2. Wang SS, Hung YT, Wen WS, Lin KC, Chen GY (2011) Exploring the inhibitory activity of short-chain phospholipids against amyloid fibrillogenesis of hen egg-white lysozyme. Biochim Biophys Acta 1811:301–313. doi:10.1016/j.bbalip.2011.02.003

    CAS  PubMed  Google Scholar 

  3. Gadad BS, Britton GB, Rao KS (2011) Targeting oligomers in neurodegenerative disorders: lessons from α-synuclein, tau, and amyloid-β peptide. J Alzheimers Dis 24:223–232. doi:10.3233/JAD-2011-110182

    CAS  PubMed  Google Scholar 

  4. Hegde ML, Hegde PM, Rao KS, Mitra S (2011) Oxidative genome damage and its repair in neurodegenerative diseases: function of transition metals as a double-edged sword. J Alzheimers Dis 24:183–198. doi:10.3233/JAD-2011-110281

    PubMed Central  CAS  PubMed  Google Scholar 

  5. Guerrero E, Padmaraju V, Hegde ML, Britton GB, Rao KS (2013) Recent advances in α-synuclein functions, advanced glycation, and toxicity: implications for Parkinson’s disease. Mol Neurobiol 47:525–536

    CAS  PubMed  Google Scholar 

  6. Prado-Prado F, García I (2012) Review of theoretical studies for prediction of neurodegenerative inhibitors. Mini Rev Med Chem 12:452–466. doi:10.2174/138955712800493780

    CAS  PubMed  Google Scholar 

  7. Cho JK, Ryu YB, Curtis-Long MJ, Ryu HW, Yuk HJ, Kim DW, Kim HJ, Lee WS, Park KH (2012) Cholinestrase inhibitory effects of geranylated flavonoids from Paulownia tomentosa fruits. Bioorg Med Chem 20:2595–2602. doi:10.1016/j.bmc.2012.02.044

    CAS  PubMed  Google Scholar 

  8. Sambamurti K, Greig NH, Utsuki T, Barnwell EL, Sharma E, Mazell C, Bhat NR, Kindy MS, Lahiri DK, Pappolla MA (2011) Targets for AD treatment: conflicting messages from γ-secretase inhibitors. J Neurochem 117:359–374. doi:10.1111/j.1471-4159.2011.07213.x

    PubMed Central  CAS  PubMed  Google Scholar 

  9. Tweedie D, Brossi A, Chen D, Ge YW, Bailey J, Yu QS, Kamal MA, Sambamurti K, Lahiri DK, Greig NH (2006) Neurine, an acetylcholine autolysis product, elevates secreted amyloid-β protein precursor and amyloid-β peptide levels, and lowers neuronal cell viability in culture: a role in Alzheimer’s disease? J Alzheimers Dis 10:9–16

    CAS  PubMed  Google Scholar 

  10. Ramesh BN, Rao TSS, Prakasam A, Sambamurti K, Rao KS (2010) Neuronutrition and Alzheimer’s disease. J Alzheimers Dis 19:1123–1139. doi:10.3233/JAD-2010-1312

    PubMed Central  CAS  PubMed  Google Scholar 

  11. Prakasam A, Muthuswamy A, Ablonczy Z, Greig NH, Fauq A, Rao KS, Pappolla MA, Sambamurti K (2010) Differential accumulation of secreted APP metabolites in ocular fluids. J Alzheimers Dis 20:1243–1253. doi:10.3233/JAD-2010-100210

    PubMed Central  CAS  PubMed  Google Scholar 

  12. Padmaraju V, Indi SS, Rao KS (2010) New evidences on Tau–DNA interactions and relevance to neurodegeneration. Neurochem Int 57:51–57. doi:10.1016/j.neuint.2010.04.013

    CAS  PubMed  Google Scholar 

  13. Barrio JR, Kepe V, Satyamurthy N, Huang SC, Small G (2008) Amyloid and tau imaging, neuronal losses and function in mild cognitive impairment. J Nutr Health Aging 12:61S–65S

    CAS  PubMed  Google Scholar 

  14. Sambamurti K, Pappolla MA, Rao KS (2008) Value in development of a TAPIR-like mouse monoclonal antibody to Aβ. J Alzheimers Dis 14:175–177

    PubMed Central  PubMed  Google Scholar 

  15. Utsuki T, Yu QS, Davidson D, Chen D, Holloway HW, Brossi A, Sambamurti K, Lahiri DK, Greig NH, Giordano T (2006) Identification of novel small molecule inhibitors of amyloid precursor protein synthesis as a route to lower Alzheimer’s disease amyloid-β peptide. J Pharmacol Exp Ther 318:855–862. doi:10.1124/jpet.106.103309

    CAS  PubMed  Google Scholar 

  16. Heredia L, Lin R, Vigo FS, Kedikian G, Busciglio J, Lorenzo A (2004) Deposition of amyloid fibrils promotes cell-surface accumulation of amyloid β precursor protein. Neurobiol Dis 16:617–629. doi:10.1016/j.nbd.2004.04.015

    CAS  PubMed  Google Scholar 

  17. Chiang K, Koo E (2014) Emerging therapeutics for Alzheimer’s disease. Annu Rev Pharmacol Toxicol 54:381–405

    CAS  PubMed  Google Scholar 

  18. Pillai JA, Cummings JL (2013) Clinical trials in predementia stages of Alzheimer disease. Med Clin North Am 97:439–457. doi:10.1016/j.mcna.2013.01.002

    PubMed  Google Scholar 

  19. Schenk D, Basi GS, Pangalos MN (2012) Treatment strategies targeting amyloid β-protein. Cold Spring Harb Perspect Med 2:a006387. doi:10.1101/cshperspect.a006387

    PubMed Central  PubMed  Google Scholar 

  20. Shi M, Caudle WM, Zhang J (2009) Biomarker discovery in neurodegenerative diseases: a proteomic approach. Neurobiol Dis 35:157–164. doi:10.1016/j.nbd.2008.09.004

    PubMed Central  CAS  PubMed  Google Scholar 

  21. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356. doi:10.1126/science.1072994

    CAS  PubMed  Google Scholar 

  22. Pallàs M, Camins A (2006) Molecular and biochemical features in Alzheimer’s disease. Curr Pharm Des 12:4389–4408

    PubMed  Google Scholar 

  23. Kumar GP, Khanum F (2012) Neuroprotective potential of phytochemicals. Pharmacogn Rev 6:81–90. doi:10.4103/0973-7847.99898

    PubMed Central  PubMed  Google Scholar 

  24. Berrocal R, Vasudevaraju P, Indi SS, Sambasiva Rao KR, Rao KS (2014) In vitro evidence that an aqueous extract of Centella asiatica modulates α-synuclein aggregation dynamics. J Alzheimers Dis 39(2):457–465. doi:10.3233/JAD-131187

    PubMed  Google Scholar 

  25. Ramesh BN, Indi SS, Rao KS (2010) Anti-amyloidogenic property of leaf aqueous extract of Caesalpinia crista. Neurosci Lett 475:110–114. doi:10.1016/j.neulet.2010.03.062

    CAS  PubMed  Google Scholar 

  26. Park SY (2010) Potential therapeutic agents against Alzheimer’s disease from natural sources. Arch Pharm Res 33:1589–1609. doi:10.1007/s12272-010-1010-y

    CAS  PubMed  Google Scholar 

  27. Fujiwara H, Tabuchi M, Yamaguchi T, Iwasaki K, Furukawa K, Sekiguchi K, Ikarashi Y, Kudo Y, Higuchi M, Saido T, Maeda S, Takashima A, Hara M, Yaegashi N, Kase Y, Arai H (2009) A traditional medicinal herb Paeonia suffruticosa and its active constituent 1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranose have potent anti-aggregation effects on Alzheimer’s amyloid beta proteins in vitro and in vivo. J Neurochem 169:1648–1657

    Google Scholar 

  28. Pérez-Jiménez J, Neveu V, Vos F, Scalbert A (2010) Systematic analysis of the content of 502 polyphenols in 452 foods and beverages: an application of the phenol-explorer database. J Agric Food Chem 58:4959–4969. doi:10.1021/jf100128b

    PubMed  Google Scholar 

  29. Harborne JB, Williams CA (2000) Advances in flavonoid research since 1992. Phytochemistry 55:481–504

    CAS  PubMed  Google Scholar 

  30. Ignat I, Volf I, Popa VI (2011) A critical review of methods for characterisation of polyphenolic compounds in fruits and vegetables. Food Chem 126:1821–1835. doi:10.1016/j.foodchem.2010.12.026

    CAS  PubMed  Google Scholar 

  31. Royer M, Diouf PN, Stevanovic T (2011) Polyphenol contents and radical scavenging capacities of red maple (Acer rubrum L.) extracts. Food Chem Toxicol 49:2180–2188. doi:10.1016/j.fct.2011.06.003

    CAS  PubMed  Google Scholar 

  32. Ghosh D, McGhie TK, Zhang J, Adaim A, Skinner M (2006) Effects of anthocyanins and other phenolics of boysenberry and blackcurrant as inhibitors of oxidative stress and damage to cellular DNA in SH-SY5Y and HL-60 cells. J Sci Food Agric 86:678–686. doi:10.1002/jsfa.2409

    CAS  Google Scholar 

  33. Hwang SL, Yen GC (2008) Neuroprotective effects of the citrus flavanones against H2O2-induced cytotoxicity in PC12 cells. J Agric Food Chem 56:859–864. doi:10.1021/jf072826r

    CAS  PubMed  Google Scholar 

  34. Heo HJ, Kim DO, Shin SC, Kim MJ, Kim BG, Shin DH (2004) Effect of antioxidant flavanone, naringenin, from Citrus junos on neuroprotection. J Agric Food Chem 52:1520–1525. doi:10.1021/jf035079g

    CAS  PubMed  Google Scholar 

  35. Murillo E, Britton GB, Durant AA (2012) Antioxidant activity and polyphenol content in cultivated and wild edible fruits grown in Panama. J Pharm Bioall Sci 4:313–317. doi:10.4103/0975-7406.103261

    Google Scholar 

  36. Candiracci M, Piatti E, Dominguez-Barragán M, García-Antrás D, Morgado B, Ruano D, Gutiérrez JF, Parrado J, Castaño A (2012) Anti-inflammatory activity of a honey flavonoid extract on lipopolysaccharide-activated N13 microglial cells. J Agric Food Chem 60:12304–12311

    CAS  PubMed  Google Scholar 

  37. Andrade JE, Burgess JR (2007) Effect of the citrus flavanone naringenin on oxidative stress in rats. J Agric Food Chem 55:2142–2148. doi:10.1021/jf061714h

    CAS  PubMed  Google Scholar 

  38. Cieślik E, Gręda A, Adamus W (2006) Contents of polyphenols in fruit and vegetables. Food Chem 94:135–142. doi:10.1016/j.foodchem.2004.11.015

    Google Scholar 

  39. Zettersten C, Co M, Wende S, Turner C, Nyholm L, Sjöberg PJR (2009) Identification and characterization of polyphenolic antioxidants using on-line liquid chromatography, electrochemistry, and electrospray ionization tandem mass spectrometry. Anal Chem 81:8968–8977. doi:10.1021/ac901397c

    CAS  PubMed  Google Scholar 

  40. Tsao R, Yang R (2003) Optimization of a new mobile phase to know the complex and real polyphenolic composition: towards a total phenolic index using high-performance liquid chromatography. J Chromatogr A 1018:29–40. doi:10.1016/j.chroma.2003.08.034

    CAS  PubMed  Google Scholar 

  41. Bravo L (1998) Polyphenols: chemistry, dietary sources, metabolism, and nutritional significance. Nutr Rev 56:317–333

    CAS  PubMed  Google Scholar 

  42. Singh MA, Arseneault MA, Sanderson T, Murthy VEN, Ramassamy C (2008) Challenges for research on polyphenols from foods in Alzheimer’s disease: bioavailability, metabolism, and cellular and molecular mechanisms. J Agric Food Chem 56:4855–4873

    CAS  PubMed  Google Scholar 

  43. Hegde ML, Bharathi P, Suram A, Venugopal C, Jagannathan R, Poddar P, Srinivas P, Sambamurti K, Rao KS, Scancar J, Messori L, Zecca L, Zatta P (2009) Challenges associated with metal chelation therapy in Alzheimer’s disease. J Alzheimers Dis 17:457–468. doi:10.3233/JAD-2009-1068

    PubMed Central  CAS  PubMed  Google Scholar 

  44. Jez JM, Bowman ME, Noel JP (2002) Expanding the biosynthetic repertoire of plant type III polyketide synthases by altering starter molecule specificity. Proc Natl Acad Sci 99:5319–5324. doi:10.1073/pnas.082590499

    PubMed Central  CAS  PubMed  Google Scholar 

  45. Chemler JA, Yan Y, Koffas MAG (2006) Biosynthesis of isoprenoids, polyunsaturated fatty acids and flavonoids in Saccharomyces cerevisiae. Microb Cell Fact 5:20. doi:10.1186/1475-2859-5-20

    PubMed Central  PubMed  Google Scholar 

  46. Tian L, Pang Y, Dixon RA (2008) Biosynthesis and genetic engineering of proanthocyanidins and (iso)flavonoids. Phytochem Rev 7:445–465. doi:10.1007/s11101-007-9076-y

    CAS  Google Scholar 

  47. Gao X, Wang P, Tang Y (2010) Engineered polyketide biosynthesis and biocatalysis in Escherichia coli. Appl Microbiol Biotechnol 88:1233–1242. doi:10.1007/s00253-010-2860-4

    PubMed Central  CAS  PubMed  Google Scholar 

  48. Ross JA, Kasum CM (2002) Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu Rev Nutr 22:19–34. doi:10.1146/annurev.nutr.22.111401.144957

    CAS  PubMed  Google Scholar 

  49. Harnly JM, Doherty RF, Beecher GR, Holden JM, Haytowitz DB, Bhagwat S, Gebhardt S (2006) Flavonoid content of U.S. fruits, vegetables, and nuts. J Agric Food Chem 54:9966–9977. doi:10.1021/jf061478a

    CAS  PubMed  Google Scholar 

  50. Vauzour D (2012) Dietary polyphenols as modulators of brain functions: biological actions and molecular mechanisms underpinning their beneficial effects. Oxid Med Cell Longev 2012:1–16. doi:10.1155/2012/914273

    Google Scholar 

  51. Wolfe KL, Liu RH (2008) Structure–activity relationships of flavonoids in the cellular antioxidant activity assay. J Agric Food Chem 56:8404–8411. doi:10.1021/jf8013074

    CAS  PubMed  Google Scholar 

  52. Manach C, Scalbert A, Morand C, Rémésy C, Jiménez L (2004) Polyphenols: food sources and bioavailability. Am J Clin Nutr 79:727–747

    CAS  PubMed  Google Scholar 

  53. El Gharras H (2009) Polyphenols: food sources, properties and applications—a review. Int J Food Sci Technol 44:2512–2518. doi:10.1111/j.1365-2621.2009.02077.x

    Google Scholar 

  54. Zapata-Torres G, Opazo F, Salgado C, Muñoz JP, Krautwurst H, Mascayano C, Sepúlveda-Boza S, Maccioni RB, Cassels BK (2004) Effects of natural flavones and flavonols on the kinase activity of Cdk5. J Nat Prod 67:416–420. doi:10.1021/np034011s

    CAS  PubMed  Google Scholar 

  55. Santos-Buelga C, Scalbert A (2000) Proanthocyanidins and tannin-like compounds—nature, occurrence, dietary intake and effects on nutrition and health. J Sci Food Agric 80(7):1094–1117

    CAS  Google Scholar 

  56. Valls J, Millán S, Martí MP, Borràs E, Arola L (2009) Advanced separation methods of food anthocyanins, isoflavones and flavanols. J Chromatogr A 1216:7143–7172. doi:10.1016/j.chroma.2009.07.030

    CAS  PubMed  Google Scholar 

  57. De Brito ES, De Araújo MCP, Alves RE, Carkeet C, Clevidence BA, Novotny JA (2007) Anthocyanins present in selected tropical fruits: acerola, jambolão, jussara, and guajiru. J Agric Food Chem 55:9389–9394. doi:10.1021/jf0715020

    PubMed  Google Scholar 

  58. Qin CG, Li Y, Niu W, Ding Y, Shang X, Xu C (2011) Composition analysis and structural identification of anthocyanins in fruit of waxberry. Czech J Food Sci 29:171–180

    CAS  Google Scholar 

  59. Chen W, Müller D, Richling E, Wink M (2013) Anthocyanin-rich purple wheat prolongs the life span of Caenorhabditis elegans probably by activating the DAF-16/FOXO transcription factor. J Agric Food Chem 61:3047–3053

    CAS  PubMed  Google Scholar 

  60. Ruberto G, Renda A, Daquino C, Amico V, Spatafora C, Tringali C, De Tommasi N (2007) Polyphenol constituents and antioxidant activity of grape pomace extracts from five Sicilian red grape cultivars. Food Chem 100:203–210. doi:10.1016/j.foodchem.2005.09.041

    CAS  Google Scholar 

  61. Shih PH, Wu CH, Yeh CT, Yen GC (2011) Protective effects of anthocyanins against amyloid β-peptide-induced damage in neuro-2A cells. J Agric Food Chem 59:1683–1689. doi:10.1021/jf302972b

    CAS  PubMed  Google Scholar 

  62. Wang JF, Lu R, Wang YZ (2010) Regulation of β cleavage of amyloid precursor protein. Neurosci Bull 26:417–427. doi:10.1007/s12264-010-0515-1

    PubMed  Google Scholar 

  63. Esler WP, Wolfe MS (2001) A portrait of Alzheimer secretases—new features and familiar faces. Science 293:1449–1454. doi:10.1126/science.1064638

    CAS  PubMed  Google Scholar 

  64. Tang BL (2005) Alzheimer’s disease: channeling APP to non-amyloidogenic processing. Biochem Biophys Res Commun 331:375–378. doi:10.1016/j.bbrc.2005.03.074

    CAS  PubMed  Google Scholar 

  65. Venugopal C, Demos CM, Rao KS, Pappolla MA (2008) Beta-secretase: structure, function, and evolution. CNS Neurol Disord Drug Targets 7:278–294

    PubMed Central  CAS  PubMed  Google Scholar 

  66. Zhou Y, Suram A, Venugopal C, Prakasam A, Lin S, Su Y, Li B, Paul SM, Sambamurti K (2008) Geranylgeranyl pyrophosphate stimulates γ-secretase to increase the generation of Aβ and APP-CTFγ. Fed Am Soc Exp Biol J 22:47–54. doi:10.1096/fj.07-8175com

    Google Scholar 

  67. Rajendran L, Schneider A, Schlechtingen G, Weidlich S, Ries J, Braxmeier T, Schwille P, Schulz JB, Schroeder C, Simons M, Jennings G, Knölker H-J, Simons K (2008) Efficient inhibition of the Alzheimer’s disease β-secretase by membrane targeting. Science 320:520–523. doi:10.1126/science.1156609

    CAS  PubMed  Google Scholar 

  68. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis J-C, Collins F, Treanor J, Rogers G, Citron M (1999) β-Secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735–741. doi:10.1126/science.286.5440.735

    CAS  PubMed  Google Scholar 

  69. Vidal R, Sammeta N, Garringer HJ, Sambamurti K, Miravalle L, Lamb BT, Ghetti B (2012) The Psen1-L166P-knock-in mutation leads to amyloid deposition in human wild-type amyloid precursor protein YAC transgenic mice. Fed Am Soc Exp Biol 26:2899–2910. doi:10.1096/fj.12-205542

    PubMed Central  CAS  PubMed  Google Scholar 

  70. Tiedt H, Lueschow A, Winter P, Müller U (2013) Previously not recognized deletion in presenilin-1 (p.Leu174del.) in a patient with early-onset familial Alzheimer’s disease. Neurosci Lett 544:115–118. doi:10.1016/j.neulet.2013.03.056

    CAS  PubMed  Google Scholar 

  71. Spasic D, Tolia A, Dillen K, Baert V, De Strooper B, Vrijens S, Annaert W (2006) Presenilin-1 maintains a nine-transmembrane topology throughout the secretory pathway. J Biol Chem 281:26569–26577. doi:10.1074/jbc.M600592200

    CAS  PubMed  Google Scholar 

  72. Utsuki T, Shoaib M, Holloway H, Ingram D, Wallace W, Haroutunian V, Sambamurti K, Lahiri D, Greig N (2002) Nicotine lowers the secretion of the Alzheimer’s amyloid beta-protein precursor that contains amyloid beta-peptide in rat. J Alzheimers Dis 4:405

    CAS  PubMed  Google Scholar 

  73. Hirohata M, Hasegawa K, Tsutsumi-Yasuhara S, Ohhashi Y, Ookoshi T, Ono K, Yamada M, Naiki H (2007) The anti-amyloidogenic effect is exerted against Alzheimer’s β-amyloid fibrils in vitro by preferential and reversible binding of flavonoids to the amyloid fibril structure. Biochemistry 46:1888–1899. doi:10.1021/bi061540x

    CAS  PubMed  Google Scholar 

  74. Ge JF, Qiao JP, Qi CC, Wang CW, Zhou JN (2012) The binding of resveratrol to monomer and fibril amyloid beta. Neurochem Int 61:1192–1201. doi:10.1016/j.neuint.2012.08.012

    CAS  PubMed  Google Scholar 

  75. Porat Y, Abramowitz A, Gazit E (2006) Inhibition of amyloid fibril formation by polyphenols: structural similarity and aromatic interactions as a common inhibition mechanism. Chem Biol Drug Des 67:27–37. doi:10.1111/j.1747-0285.2005.00318.x

    CAS  PubMed  Google Scholar 

  76. Jung HA, Oh SH, Choi JS (2010) Molecular docking studies of phlorotannins from Eisenia bicyclis with BACE1 inhibitory activity. Bioorg Med Chem Lett 20:3211–3215. doi:10.1016/j.bmcl.2010.04.093

    CAS  PubMed  Google Scholar 

  77. Postina R, Schroeder A, Dewachter I, Bohl J, Schmitt U, Kojro E, Prinzen C, Endres K, Hiemke C, Blessing M, Flamez P, Dequenne A, Godaux E, van Leuven F, Fahrenholz F (2004) A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J Clin Invest 113:1456–1464. doi:10.1172/JCI200420864.1456

    PubMed Central  CAS  PubMed  Google Scholar 

  78. Endres K, Fahrenholz F (2012) Regulation of alpha-secretase ADAM10 expression and activity. Exp Brain Res 217:343–352. doi:10.1007/s00221-011-2885-7

    CAS  PubMed  Google Scholar 

  79. Endres K, Fahrenholz F (2010) Upregulation of the α-secretase ADAM10—risk or reason for hope? Fed Eur Biochem Soc J 277:1585–1596. doi:10.1111/j.1742-4658.2010.07566.x

    CAS  Google Scholar 

  80. Skovronsky DM, Moore DB, Milla ME, Doms RW, Lee VM (2000) Protein kinase C-dependent α-secretase competes with β-secretase for cleavage of amyloid-β precursor protein in the trans-golgi network. J Biol Chem 275:2568–2575

    CAS  PubMed  Google Scholar 

  81. Tian S, Jianhua W (2010) Comparative study of the binding pockets of mammalian proprotein convertases and its implications for the design of specific small molecule inhibitors. Int J Biol Sci 6:89–95

    PubMed Central  PubMed  Google Scholar 

  82. Anders A, Gilbert S, Garten W, Postina R, Fahrenholz F (2001) Regulation of the α-secretase ADAM10 by its prodomain and proprotein convertases. Fed Am Soc Exp Biol J 15:1837–1839. doi:10.1096/fj.01

    CAS  Google Scholar 

  83. Edwards DR, Handsley MM, Pennington CJ (2008) The ADAM metalloproteinases. Mol Aspects Med 29:258–289. doi:10.1016/j.mam.2008.08.001

    CAS  PubMed  Google Scholar 

  84. Zhong M, Munzer JS, Basak A, Benjannet S, Mowla SJ, Decroly E, Chrétien M, Seidah NG (1999) The prosegments of furin and PC7 as potent inhibitors of proprotein convertases. In vitro and ex vivo assessment of their efficacy and selectivity. J Biol Chem 274:33913–33920

    CAS  PubMed  Google Scholar 

  85. Kang IJ, Jang BG, In S, Choi B, Kim M, Kim MJ (2013) Phlorotannin-rich Ecklonia cava reduces the production of beta-amyloid by modulating alpha- and gamma-secretase expression and activity. Neurotoxicology 34:16–24. doi:10.1016/j.neuro.2012.09.013

    CAS  PubMed  Google Scholar 

  86. Rezai-Zadeh K, Shytle D, Sun N, Mori T, Hou H, Jeanniton D, Ehrhart J, Townsend K, Zeng J, Morgan D, Hardy J, Town T, Tan J (2005) Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice. J Neurosci 25:8807–8814. doi:10.1523/JNEUROSCI.1521-05.2005

    CAS  PubMed  Google Scholar 

  87. Hartman RE, Shah A, Fagan AM, Schwetye KE, Parsadanian M, Schulman RN, Finn MB, Holtzman DM (2006) Pomegranate juice decreases amyloid load and improves behavior in a mouse model of Alzheimer’s disease. Neurobiol Dis 24:506–515. doi:10.1016/j.nbd.2006.08.006

    CAS  PubMed  Google Scholar 

  88. Vestling M, Cedazo-Mínguez Á, Adem A, Wiehager B, Racchi M, Lannfelt L, Cowburn RF (1999) Protein kinase C and amyloid precursor protein processing in skin fibroblasts from sporadic and familial Alzheimer’s disease cases. Biochim Biophys Acta 1453:341–350

    CAS  PubMed  Google Scholar 

  89. Narasingapa RB, Jargaval MR, Pullabhatla S, Htoo HH, Rao KS, Hernandez JF, Govitrapong P, Vincent B (2012) Activation of α-secretase by curcumin-aminoacid conjugates. Biochem Biophys Res Commun 424:691–696. doi:10.1016/j.bbrc.2012.07.010

    CAS  PubMed  Google Scholar 

  90. Levites Y, Amit T, Mandel S, Youdim MBH (2003) Neuroprotection and neurorescue against Aβ toxicity and PKC-dependent release of non-amyloidogenic soluble precursor protein by green tea polyphenol (-)-epigallocatechin-3-gallate. Fed Am Soc Exp Biol J 17:952–958

    CAS  Google Scholar 

  91. Mancini F, De Simone A, Andrisano V (2011) Beta-secretase as a target for Alzheimer’s disease drug discovery: an overview of in vitro methods for characterization of inhibitors. Anal Bioanal Chem 400:1979–1996. doi:10.1007/s00216-011-4963-x

    CAS  PubMed  Google Scholar 

  92. Shimizu H, Tosaki A, Kaneko K, Hisano T, Sakurai T, Nukina N (2008) Crystal structure of an active form of BACE1, an enzyme responsible for amyloid β protein production. Mol Cell Biol 28:3663–3671. doi:10.1128/MCB.02185-07

    PubMed Central  CAS  PubMed  Google Scholar 

  93. Yu N, Hayik SA, Wang B, Liao N, Reynolds CH, Merz KM (2006) Assigning the protonation states of the key aspartates in β-secretase using QM/MM X-ray structure refinement. J Chem Theory Comput 2:1057–1069. doi:10.1021/ct0600060

    PubMed Central  CAS  PubMed  Google Scholar 

  94. Stachel SJ, Coburn CA, Steele TG, Jones KG, Loutzenhiser EF, Gregro AR, Rajapakse HA, Lai MT, Crouthamel MC, Xu M, Tugusheva K, Lineberger JE, Pietrak BL, Espeseth AS, Shi XP, Chen-Dodson E, Holloway MK, Munshi S, Simon AJ, Kuo L, Vacca JP (2004) Structure-based design of potent and selective cell-permeable inhibitors of human β-secretase (BACE-1). J Med Chem 47:6447–6450. doi:10.1021/jm049379g

    CAS  PubMed  Google Scholar 

  95. Chakraborty S, Kumar S, Basu S (2011) Conformational transition in the substrate binding domain of β-secretase exploited by NMA and its implication in inhibitor recognition: BACE1-myricetin a case study. Neurochem Int 58:914–923. doi:10.1016/j.neuint.2011.02.021

    CAS  PubMed  Google Scholar 

  96. Marcinkeviciene J, Luo Y, Graciani NR, Combs AP, Copeland RA (2001) Mechanism of inhibition of β-site amyloid precursor protein-cleaving enzyme (BACE) by a statine-based peptide. J Biol Chem 276:23790–23794. doi:10.1074/jbc.M101896200

    CAS  PubMed  Google Scholar 

  97. Haass C, De Strooper B (1999) The presenilins in Alzheimer’s disease—proteolysis holds the key. Science 286:916–919. doi:10.1126/science.286.5441.916

    CAS  PubMed  Google Scholar 

  98. Gazit E (2002) A possible role for π-stacking in the self-assembly of amyloid fibrils. Fed Am Soc Exp Biol J 16:77–83. doi:10.1096/fj.01-0442hyp

    CAS  Google Scholar 

  99. Doran TM, Anderson EA, Latchney SE, Opanashuk LA, Nilsson BL (2012) An azobenzene photoswitch sheds light on turn nucleation in amyloid-β self-assembly. ACS Chem Neurosci 3:211–220. doi:10.1021/cn2001188

    PubMed Central  CAS  PubMed  Google Scholar 

  100. Bett CK, Ngunjiri JN, Serem WK, Fontenot KR, Hammer RP, McCarley RL, Garno JC (2010) Structure-activity relationships in peptide modulators of β-amyloid protein aggregation: variation in α, α-disubstitution results in altered aggregate size and morphology. ACS Chem Neurosci 1:608–626. doi:10.1021/cn100045q

    PubMed Central  CAS  PubMed  Google Scholar 

  101. Tycko R, Wickner RB (2013) Molecular structures of amyloid and prion fibrils: consensus versus controversy. Acc Chem Res 46:1487–1496. doi:10.1021/ar300282r

    PubMed Central  CAS  PubMed  Google Scholar 

  102. Wang Q, Yu X, Patal K, Hu R, Chuang S, Zhang G, Zheng J (2013) Tanshinones inhibit amyloid aggregation by amyloid-β peptide, disaggregate amyloid fibrils, and protect cultured cells. ACS Chem Neurosci 4:1004–1015. doi:10.1021/cn400051e

    PubMed Central  CAS  PubMed  Google Scholar 

  103. Ashburn TT, Han H, McGuinness BF, Lansbury PT (1996) Amyloid probes based on Congo Red distinguish between fibrils comprising different peptides. Chem Biol 3:351–358

    CAS  PubMed  Google Scholar 

  104. Wetzel R, Shivaprasad S, Williams AD (2007) Plasticity of amyloid fibrils. Biochemistry 46:1–10

    PubMed Central  CAS  PubMed  Google Scholar 

  105. Ma J, Komatsu H, Kim YS, Liu L, Hochstrasser RM, Axelsen PH (2013) Intrinsic structural heterogeneity and long-term maturation of amyloid β peptide fibrils. ACS Chem Neurosci 4:1236–1243. doi:10.1021/cn400092v

    PubMed Central  CAS  PubMed  Google Scholar 

  106. Sambamurti K, Rao KS, Pappolla MA (2009) Frontiers in the pathogenesis of Alzheimer’s disease. Indian J Psychiatry 51:S56–S60

    PubMed Central  PubMed  Google Scholar 

  107. Bett CK, Serem WK, Fontenot KR, Hammer RP, Garno JC (2010) Effects of peptides derived from terminal modifications of the Aβ central hydrophobic core on Aβ fibrillization. ACS Chem Neurosci 1:661–678. doi:10.1021/cn900019r

    PubMed Central  CAS  PubMed  Google Scholar 

  108. Jagota S, Rajadas J (2011) The role of Pro, Gly Lys, and Arg containing peptides on amyloid-beta aggregation. Int J Pept Res Ther 18:53–61. doi:10.1007/s10989-011-9278-4

    Google Scholar 

  109. Geng J, Li M, Wu L, Ren J, Qu X (2012) Liberation of copper from amyloid plaques: making a risk factor useful for Alzheimer’s disease treatment. J Med Chem 55:9146–9155. doi:10.1021/jm3003813

    CAS  PubMed  Google Scholar 

  110. Glabe CC (2005) Amyloid accumulation and pathogensis of Alzheimer’s disease: significance of monomeric, oligomeric and fibrillar Aβ. Subcell Biochem 38:167–177

    CAS  PubMed  Google Scholar 

  111. Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, Chen P, Kayed R, Glabe CG, Frautschy SA, Cole GM (2005) Curcumin inhibits formation of amyloid β oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem 280:5892–5901. doi:10.1074/jbc.M404751200

    CAS  PubMed  Google Scholar 

  112. Gupta VB, Rao KS (2007) Anti-amyloidogenic activity of S-allyl-L-cysteine and its activity to destabilize Alzheimer’s β-amyloid fibrils in vitro. Neurosci Lett 429:75–80. doi:10.1016/j.neulet.2007.09.042

    CAS  PubMed  Google Scholar 

  113. Chromy BA, Nowak RJ, Lambert MP, Viola KL, Chang L, Velasco PT, Jones BW, Fernandez SJ, Lacor PN, Horowitz P, Finch CE, Krafft GA, Klein WL (2003) Self-assembly of Aβ1-42 into globular neurotoxins. Biochemistry 42:12749–12760. doi:10.1021/bi030029q

    CAS  PubMed  Google Scholar 

  114. Yamaguchi T, Yagi H, Goto Y, Matsuzaki K, Hoshino M (2010) A disulfide-linked amyloid-β peptide dimer forms a protofibril-like oligomer through a distinct pathway from amyloid fibril formation. Biochemistry 49:7100–7107

    CAS  PubMed  Google Scholar 

  115. Citron M (2010) Alzheimer’s disease: strategies for disease modification. Nat Rev Drug Discov 9:387–398. doi:10.1038/nrd2896

    CAS  PubMed  Google Scholar 

  116. Cabaleiro-Lago C, Quinlan-Pluck F, Lynch I, Dawson KA, Linse S (2010) Dual effect of amino modified polystyrene nanoparticles on amyloid β protein fibrillation. ACS Chem Neurosci 1:279–287. doi:10.1021/cn900027u

    PubMed Central  CAS  PubMed  Google Scholar 

  117. Necula M, Kayed R, Milton S, Glabe CG (2007) Small molecule inhibitors of aggregation indicate that amyloid β oligomerization and fibrillization pathways are independent and distinct. J Biol Chem 282:10311–10324. doi:10.1074/jbc.M608207200

    CAS  PubMed  Google Scholar 

  118. Chaudhary N, Singh S, Nagaraj R (2011) Aggregation properties of a short peptide that mediates amyloid fibril formation in model proteins unrelated to disease. J Biosci 36:679–689. doi:10.1007/s12038-011-9104-3

    CAS  PubMed  Google Scholar 

  119. Sinha S, Lopes DHJ, Bitan G (2012) A key role for lysine residues in amyloid β-protein folding, assembly, and toxicity. ACS Chem Neurosci 3:473–481

    PubMed Central  CAS  PubMed  Google Scholar 

  120. Bazoti FN, Bergquist J, Markides K, Tsarbopoulos A (2008) Localization of the noncovalent binding site between amyloid-β-peptide and oleuropein using electrospray ionization FT-ICR mass spectrometry. J Am Soc Mass Spectrom 19:1078–1085. doi:10.1016/j.jasms.2008.03.011

    CAS  PubMed  Google Scholar 

  121. Hudson SA, Ecroyd H, Dehle FC, Musgrave IF, Carver JA (2009) (−)-Epigallocatechin-3-Gallate (EGCG) maintains κ-casein in its pre-fibrillar state without redirecting its aggregation pathway. J Mol Biol 392:689–700

    CAS  PubMed  Google Scholar 

  122. Dolai S, Shi W, Corbo C, Sun C, Averick S, Obeysekera D, Farid M, Alonso A, Banerjee P, Raja K (2011) “Clicked” sugar–curcumin conjugate: modulator of amyloid-β and tau peptide aggregation at ultralow concentrations. ACS Chem Neurosci 2:694–699

    PubMed Central  CAS  PubMed  Google Scholar 

  123. Porat Y, Mazor Y, Efrat S, Gazit E (2004) Inhibition of islet amyloid polypeptide fibril formation: a potential role for heteroaromatic interactions. Biochemistry 43:14454–14462

    CAS  PubMed  Google Scholar 

  124. Convertino M, Pellarin R, Catto M, Carotti A, Caflisch A (2009) 9,10-Anthraquinone hinders beta β-aggregation: how does a small molecule interfere with Aβ-peptide amyloid fibrillation? Protein Sci 18:792–800. doi:10.1002/pro.87

    PubMed Central  CAS  PubMed  Google Scholar 

  125. Rivière C, Delaunay JC, Immel F, Cullin C, Monti JP (2009) The polyphenol piceid destabilizes preformed amyloid fibrils and oligomers in vitro: hypothesis on possible molecular mechanisms. Neurochem Res 34:1120–1128. doi:10.1007/s11064-008-9883-6

    PubMed  Google Scholar 

  126. Wong HE, Qi W, Choi HM, Fernandez EJ, Kwon I (2011) A safe, blood-brain barrier permeable triphenylmethane dye inhibits amyloid-β neurotoxicity by generating nontoxic aggregates. ACS Chem Neurosci 2:645–657. doi:10.1021/cn200056g

    PubMed Central  CAS  PubMed  Google Scholar 

  127. Katayama S, Ogawa H, Nakamura S (2011) Apricot carotenoids possess potent anti-amyloidogenic activity in vitro. J Agric Food Chem 59:12691–12696. doi:10.1021/jf203654c

    CAS  PubMed  Google Scholar 

  128. Wang YJ, Thomas P, Zhong JH, Bi FF, Kosaraju S, Pollard A, Fenech M, Zhou XF (2009) Consumption of grape seed extract prevents amyloid-β deposition and attenuates inflammation in brain of an Alzheimer’s disease mouse. Neurotox Res 15:3–14. doi:10.1007/s12640-009-9000-x

    PubMed  Google Scholar 

  129. Marin E, Briceño MI, Caballero-George C (2013) Critical evaluation of biodegradable polymers used in nanodrugs. Int J Nanomedicine 8:3071–3091. doi:10.2147/IJN.S47186

    PubMed Central  PubMed  Google Scholar 

  130. Feng Y, Wang XP, Yang SG, Wang YJ, Zhang X, Du XT, Sun XX, Zhao M, Huang L, Liu RT (2009) Resveratrol inhibits beta-amyloid oligomeric cytotoxicity but does not prevent oligomer formation. Neurotoxicology 30:986–995. doi:10.1016/j.neuro.2009.08.013

    CAS  PubMed  Google Scholar 

  131. Ono K, Yoshiike Y, Takashima A, Hasegawa K, Naiki H, Yamada M (2003) Potent anti-amyloidogenic and fibril-destabilizing effects of polyphenols in vitro: implications for the prevention and therapeutics of Alzheimer’s disease. J Neurochem 87:172–181. doi:10.1046/j.1471-4159.2003.01976.x

    CAS  PubMed  Google Scholar 

  132. Rivière C, Richard T, Vitrac X, Mérillon JM, Valls J, Monti JP (2008) New polyphenols active on β-amyloid aggregation. Bioorg Med Chem Lett 18:828–831. doi:10.1016/j.bmcl.2007.11.028

    PubMed  Google Scholar 

  133. Shoval H, Weiner L, Gazit E, Levy M, Pinchuk I, Lichtenberg D (2008) Polyphenol-induced dissociation of various amyloid fibrils results in a methionine-independent formation of ROS. Biochim Biophys Acta 1784:1570–1577. doi:10.1016/j.bbapap.2008.08.007

    CAS  PubMed  Google Scholar 

  134. Akaishi T, Morimoto T, Shibao M, Watanabe S, Sakai-Kato K, Utsunomiya-Tate N, Abe K (2008) Structural requirements for the flavonoid fisetin in inhibiting fibril formation of amyloid β protein. Neurosci Lett 444:280–285. doi:10.1016/j.neulet.2008.08.052

    CAS  PubMed  Google Scholar 

  135. Henry-Vitrac C, Berbille H, Mérillon JM, Vitrac X (2010) Soy isoflavones as potential inhibitors of Alzheimer β-amyloid fibril aggregation in vitro. Food Res Int 43:2176–2178. doi:10.1016/j.foodres.2010.07.032

    CAS  Google Scholar 

  136. Carver JA, Duggan PJ, Ecroyd H, Liu Y, Meyer AG, Tranberg CE (2010) Carboxymethylated-k-casein: a convenient tool for the identification of polyphenolic inhibitors of amyloid fibril formation. Bioorg Med Chem 18:222–228. doi:10.1016/j.bmc.2009.10.063

    CAS  PubMed  Google Scholar 

  137. Rivière C, Richard T, Quentin L, Krisa S, Mérillon JM, Monti JP (2007) Inhibitory activity of stilbenes on Alzheimer’s β-amyloid fibrils in vitro. Bioorg Med Chem 15:1160–1167. doi:10.1016/j.bmc.2006.09.069

    PubMed  Google Scholar 

  138. Rivière C, Papastamoulis Y, Fortin PY, Delchier N, Andriamanarivo S, Waffo-Teguo P, Kapche GD, Amira-Guebalia H, Delaunay JC, Mérillon JM, Richard T, Monti JP (2010) New stilbene dimers against amyloid fibril formation. Bioorg Med Chem Lett 20:3441–3443. doi:10.1016/j.bmcl.2009.09.074

    PubMed  Google Scholar 

  139. Ono K, Hamaguchi T, Naiki H, Yamada M (2006) Anti-amyloidogenic effects of antioxidants: implications for the prevention and therapeutics of Alzheimer’s disease. Biochim Biophys Acta 1762:575–586. doi:10.1016/j.bbadis.2006.03.002

    CAS  PubMed  Google Scholar 

  140. Ono K, Hasegawa K, Naiki H, Yamada M (2004) Anti-amyloidogenic activity of tannic acid and its activity to destabilize Alzheimer’s β-amyloid fibrils in vitro. Biochim Biophys Acta 1690:193–202

    CAS  PubMed  Google Scholar 

  141. Ono K, Yamada M (2006) Antioxidant compounds have potent anti-fibrillogenic and fibril-destabilizing effects for α-synuclein fibrils in vitro. J Neurochem 97:105–115. doi:10.1111/j.1471-4159.2006.03707.x

    CAS  PubMed  Google Scholar 

  142. Ono K, Naiki H, Yamada M (2006) The development of preventives and therapeutics for Alzheimer’s disease that inhibit the formation of β-amyloid fibrils (fAβ), as well as destabilize preformed fAβ. Curr Pharm Des 12:4357–4375

    CAS  PubMed  Google Scholar 

  143. Richard T, Poupard P, Nassra M, Papastamoulis Y, Iglésias ML, Krisa S, Waffo-Teguo P, Mérillon JM, Monti JP (2011) Protective effect of ε-viniferin on β-amyloid peptide aggregation investigated by electrospray ionization mass spectrometry. Bioorg Med Chem 19:3152–3155. doi:10.1016/j.bmc.2011.04.001

    CAS  PubMed  Google Scholar 

  144. Frid P, Anisimov SV, Popovic N (2007) Congo red and protein aggregation in neurodegenerative diseases. Brain Res Rev 53:135–160. doi:10.1016/j.brainresrev.2006.08.001

    CAS  PubMed  Google Scholar 

  145. Richard T, Papastamoulis Y, Waffo-Teguo P, Monti JP (2013) 3D NMR structure of a complex between the amyloid beta peptide (1–40) and the polyphenol ε-viniferin glucoside: implications in Alzheimer’s disease. Biochim Biophys Acta 1830:5068–5074. doi:10.1016/j.bbagen.2013.06.031

    CAS  PubMed  Google Scholar 

  146. D’Archivio M, Filesi C, Varì R, Scazzocchio B, Masella R (2010) Bioavailability of the polyphenols: status and controversies. Int J Mol Sci 11:1321–1342. doi:10.3390/ijms11041321

    PubMed Central  PubMed  Google Scholar 

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Acknowledgments

Johant Lakey is supported by a doctoral scholarship granted by the Institute for Training and Development of Human Resources of Panama (IFARHU) and National Secretariat for Science, Technology, and Innovation of Panama (SENACYT). K.S Rao is grateful to the National Science System (SNI) of SENACYT for the financial support.

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Correspondence to K. S. Rao or Armando A. Durant.

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Johant Lakey-Beitia and Ruben Berrocal are equally first authors

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Lakey-Beitia, J., Berrocal, R., Rao, K.S. et al. Polyphenols as Therapeutic Molecules in Alzheimer’s Disease Through Modulating Amyloid Pathways. Mol Neurobiol 51, 466–479 (2015). https://doi.org/10.1007/s12035-014-8722-9

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