Biophysical Reviews

, Volume 11, Issue 6, pp 901–925 | Cite as

Recent advances in the design and applications of amyloid-β peptide aggregation inhibitors for Alzheimer’s disease therapy

  • Safura Jokar
  • Saeedeh Khazaei
  • Hossein Behnammanesh
  • Amir Shamloo
  • Mostafa Erfani
  • Davood Beiki
  • Omid BaviEmail author


Alzheimer’s disease (AD) is an irreversible neurological disorder that progresses gradually and can cause severe cognitive and behavioral impairments. This disease is currently considered a social and economic incurable issue due to its complicated and multifactorial characteristics. Despite decades of extensive research, we still lack definitive AD diagnostic and effective therapeutic tools. Consequently, one of the most challenging subjects in modern medicine is the need for the development of new strategies for the treatment of AD. A large body of evidence indicates that amyloid-β (Aβ) peptide fibrillation plays a key role in the onset and progression of AD. Recent studies have reported that amyloid hypothesis–based treatments can be developed as a new approach to overcome the limitations and challenges associated with conventional AD therapeutics. In this review, we will provide a comprehensive view of the challenges in AD therapy and pathophysiology. We also discuss currently known compounds that can inhibit amyloid-β (Aβ) aggregation and their potential role in advancing current AD treatments. We have specifically focused on Aβ aggregation inhibitors including metal chelators, nanostructures, organic molecules, peptides (or peptide mimics), and antibodies. To date, these molecules have been the subject of numerous in vitro and in vivo assays as well as molecular dynamics simulations to explore their mechanism of action and the fundamental structural groups involved in Aβ aggregation. Ultimately, the aim of these studies (and current review) is to achieve a rational design for effective therapeutic agents for AD treatment and diagnostics.


Neurodegenerative diseases Amyloid-β fibrillation Metal chelators Nanotechnology Peptide inhibitors Computational methods 



We would like to thank the Editorial Board Members of the Biophysical Reviews journal for their help in improving the clarity of expression of our manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. Adlard PA, Cherny RA, Finkelstein DI, Gautier E, Robb E, Cortes M, Volitakis I, Liu X, Smith JP, Perez K (2008) Rapid restoration of cognition in Alzheimer’s transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Aβ. Neuron 59(1):43–55PubMedGoogle Scholar
  2. Ahmad E, Ahmad A, Singh S, Arshad M, Khan AH, Khan RH (2011) A mechanistic approach for islet amyloid polypeptide aggregation to develop anti-amyloidogenic agents for type-2 diabetes. Biochimie 93(5):793–805PubMedGoogle Scholar
  3. Ahmad Fazili N, Naeem A, Hua Gan S, Kamal MA (2015) Therapeutic interventions for the suppression of Alzheimer’s disease: quest for a remedy. Curr Drug Metab 16(5):346–353Google Scholar
  4. Aloisi A, Barca A, Romano A, Guerrieri S, Storelli C, Rinaldi R, Verri T (2013) Anti-aggregating effect of the naturally occurring dipeptide carnosine on aβ1-42 fibril formation. PLoS One 8(7):e68159PubMedPubMedCentralGoogle Scholar
  5. Amijee H, Bate C, Williams A, Virdee J, Jeggo R, Spanswick D, Scopes DI, Treherne JM, Mazzitelli S, Chawner R (2012) The N-methylated peptide SEN304 powerfully inhibits Aβ (1–42) toxicity by perturbing oligomer formation. Biochemistry 51(42):8338–8352PubMedGoogle Scholar
  6. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB (2007) Bioavailability of curcumin: problems and promises. Mol Pharm 4(6):807–818PubMedGoogle Scholar
  7. Anguiano M, Nowak RJ, Lansbury PT (2002) Protofibrillar islet amyloid polypeptide permeabilizes synthetic vesicles by a pore-like mechanism that may be relevant to type II diabetes. Biochemistry 41(38):11338–11343PubMedGoogle Scholar
  8. Ansari MA, Abdul HM, Joshi G, Opii WO, Butterfield DA (2009) Protective effect of quercetin in primary neurons against Aβ (1–42): relevance to Alzheimer’s disease. J Nutr Biochem 20(4):269–275PubMedGoogle Scholar
  9. Aoraha E, Candreva J, Kim JR (2015) Engineering of a peptide probe for β-amyloid aggregates. Mol BioSyst 11(8):2281–2289PubMedGoogle Scholar
  10. Ashur-Fabian O, Segal-Ruder Y, Skutelsky E, Brenneman DE, Steingart RA, Giladi E, Gozes I (2003) The neuroprotective peptide NAP inhibits the aggregation of the beta-amyloid peptide. Peptides 24(9):1413–1423PubMedPubMedCentralGoogle Scholar
  11. Association A s (2016) 2016 Alzheimer’s disease facts and figures. Alzheimers Dement 12(4):459–509Google Scholar
  12. Atwood CS, Moir RD, Huang X, Scarpa RC, Bacarra NME, Romano DM, Hartshorn MA, Tanzi RE, Bush AI (1998) Dramatic aggregation of Alzheimer Aβ by Cu (II) is induced by conditions representing physiological acidosis. J Biol Chem 273(21):12817–12826PubMedGoogle Scholar
  13. Atwood CS, Scarpa RC, Huang X, Moir RD, Jones WD, Fairlie DP, Tanzi RE, Bush AI (2000) Characterization of copper interactions with Alzheimer amyloid β peptides: identification of an attomolar-affinity copper binding site on amyloid β1-42. J Neurochem 75(3):1219–1233PubMedGoogle Scholar
  14. Austen BM, Paleologou KE, Ali SA, Qureshi MM, Allsop D, El-Agnaf OM (2008) Designing peptide inhibitors for oligomerization and toxicity of Alzheimer’s β-amyloid peptide. Biochemistry 47(7):1984–1992PubMedGoogle Scholar
  15. Bansal S, Maurya IK, Yadav N, Thota CK, Kumar V, Tikoo K, Chauhan VS, Jain R (2016) C-terminal fragment, Aβ32–37, analogues protect against aβ aggregation-induced toxicity. ACS Chem Neurosci 7(5):615–623PubMedGoogle Scholar
  16. Bartus RT, Emerich DF (1999) Cholinergic markers in Alzheimer disease. Jama 282(23):2208–2209PubMedGoogle Scholar
  17. Bekris LM, Yu C-E, Bird TD, Tsuang DW (2010) Genetics of Alzheimer disease. J Geriatr Psychiatry Neurol 23(4):213–227PubMedPubMedCentralGoogle Scholar
  18. Belluti F, Rampa A, Gobbi S, Bisi A (2013) Small-molecule inhibitors/modulators of amyloid-β peptide aggregation and toxicity for the treatment of Alzheimer’s disease: a patent review (2010–2012). Expert Opin Ther Patents 23(5):581–596Google Scholar
  19. Bieschke J, Russ J, Friedrich RP, Ehrnhoefer DE, Wobst H, Neugebauer K, Wanker EE (2010) EGCG remodels mature α-synuclein and amyloid-β fibrils and reduces cellular toxicity. Proc Natl Acad Sci 107(17):7710–7715PubMedGoogle Scholar
  20. Boridy S, Takahashi H, Akiyoshi K, Maysinger D (2009) The binding of pullulan modified cholesteryl nanogels to Aβ oligomers and their suppression of cytotoxicity. Biomaterials 30(29):5583–5591PubMedGoogle Scholar
  21. Brahmachari S, Paul A, Segal D, Gazit E (2017) Inhibition of amyloid oligomerization into different supramolecular architectures by small molecules: mechanistic insights and design rules. Future Med Chem 9(8):797–810PubMedGoogle Scholar
  22. Brahmkhatri VP, Sharma N, Sunanda P, D’Souza A, Raghothama S, Atreya HS (2018) Curcumin nanoconjugate inhibits aggregation of N-terminal region (Aβ-16) of an amyloid beta peptide. New J Chem 42(24):19881–19892Google Scholar
  23. Brener O, Dunkelmann T, Gremer L, Van Groen T, Mirecka EA, Kadish I, Willuweit A, Kutzsche J, Jürgens D, Rudolph S (2015) QIAD assay for quantitating a compound’s efficacy in elimination of toxic Aβ oligomers. Sci Rep 5:13222PubMedPubMedCentralGoogle Scholar
  24. Bruce NJ, Chen D, Dastidar SG, Marks GE, Schein CH, Bryce RA (2010) Molecular dynamics simulations of Aβ fibril interactions with β-sheet breaker peptides. Peptides 31(11):2100–2108PubMedGoogle Scholar
  25. Bruno BJ, Miller GD, Lim CS (2013) Basics and recent advances in peptide and protein drug delivery. Ther Deliv 4(11):1443–1467PubMedPubMedCentralGoogle Scholar
  26. 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(4):279–287PubMedPubMedCentralGoogle Scholar
  27. Cabaleiro-Lago C, Quinlan-Pluck F, Lynch I, Lindman S, Minogue AM, Thulin E, Walsh DM, Dawson KA, Linse S (2008) Inhibition of amyloid β protein fibrillation by polymeric nanoparticles. J Am Chem Soc 130(46):15437–15443PubMedGoogle Scholar
  28. Casdorph H (1981) EDTA chelation therapy II, efficacy in brain disorders. J Holist Med 3:101–117Google Scholar
  29. Chauhan NB, Siegel GJ (2007) Antisense inhibition at the β-secretase-site of β-amyloid precursor protein reduces cerebral amyloid and acetyl cholinesterase activity in Tg2576. Neuroscience 146(1):143–151PubMedPubMedCentralGoogle Scholar
  30. Chen T, Zhang Y, Shang Y, Gu X, Zhu Y, Zhu L (2018) NBD-BPEA regulates Zn2+-or Cu2+-induced Aβ40 aggregation and cytotoxicity. Food Chem Toxicol 119:260–267PubMedGoogle Scholar
  31. Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD, McLean CA, Barnham KJ, Volitakis I, Fraser FW, Kim Y-S (2001) Treatment with a copper-zinc chelator markedly and rapidly inhibits β-amyloid accumulation in Alzheimer’s disease transgenic mice. Neuron 30(3):665–676PubMedGoogle Scholar
  32. Chorev M, Goodman M (1995) Recent developments in retro peptides and proteins—an ongoing topochemical exploration. Trends Biotechnol 13(10):438–445PubMedGoogle Scholar
  33. Churches QI, Caine J, Cavanagh K, Epa VC, Waddington L, Tranberg CE, Meyer AG, Varghese JN, Streltsov V, Duggan PJ (2014) Naturally occurring polyphenolic inhibitors of amyloid beta aggregation. Bioorg Med Chem Lett 24(14):3108–3112PubMedGoogle Scholar
  34. Cimini S, Sclip A, Mancini S, Colombo L, Messa M, Cagnotto A, Di Fede G, Tagliavini F, Salmona M, Borsello T (2016) The cell-permeable Aβ1-6A2VTAT (D) peptide reverts synaptopathy induced by Aβ1-42wt. Neurobiol Dis 89:101–111PubMedGoogle Scholar
  35. Civitelli L, Sandin L, Nelson E, Khattak SI, Brorsson A-C, Kågedal K (2016) The luminescent oligothiophene p-FTAA converts toxic Aβ1–42 species into nontoxic amyloid fibers with altered properties. J Biol Chem 291(17):9233–9243PubMedPubMedCentralGoogle Scholar
  36. Colovic MB, Krstic DZ, Lazarevic-Pasti TD, Bondzic AM, Vasic VM (2013) Acetylcholinesterase inhibitors: pharmacology and toxicology. Curr Neuropharmacol 11(3):315–335PubMedPubMedCentralGoogle Scholar
  37. Conte-Daban A, Boff B, Candido Matias A, Aparicio CNM, Gateau C, Lebrun C, Cerchiaro G, Kieffer I, Sayen S, Guillon E (2017) A trishistidine pseudopeptide with ability to remove both CuΙ and CuΙΙ from the amyloid-β peptide and to stop the associated ROS formation. Chem Eur J 23(67):17078–17088PubMedGoogle Scholar
  38. Corder E, Saunders AM, Risch N, Strittmatter W, Schmechel D, Gaskell P, Rimmler J, Locke P, Conneally P, Schmader K (1994) Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet 7(2):180PubMedGoogle Scholar
  39. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small G, Roses AD, Haines J, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261(5123):921–923PubMedGoogle Scholar
  40. Crouch PJ, Barnham KJ (2012) Therapeutic redistribution of metal ions to treat Alzheimer’s disease. Acc Chem Res 45(9):1604–1611PubMedGoogle Scholar
  41. Cruz M, Tusell J, Grillo-Bosch D, Albericio F, Serratosa J, Rabanal F, Giralt E (2004) Inhibition of β-amyloid toxicity by short peptides containing N-methyl amino acids. J Pept Res 63(3):324–328PubMedGoogle Scholar
  42. Cui L, Cai Y, Cheng W, Liu G, Zhao J, Cao H, Tao H, Wang Y, Yin M, Liu T (2017) A novel, multi-target natural drug candidate, matrine, improves cognitive deficits in Alzheimer’s disease transgenic mice by inhibiting Aβ aggregation and blocking the RAGE/Aβ Axis. Mol Neurobiol 54(3):1939–1952PubMedGoogle Scholar
  43. Cui Z, Lockman PR, Atwood CS, Hsu C-H, Gupte A, Allen DD, Mumper RJ (2005) Novel D-penicillamine carrying nanoparticles for metal chelation therapy in Alzheimer’s and other CNS diseases. Eur J Pharm Biopharm 59(2):263–272PubMedGoogle Scholar
  44. Danho, W., J. Swistok, W. Khan, X.-J. Chu, A. Cheung, D. Fry, H. Sun, G. Kurylko, L. Rumennik and J. Cefalu (2009). Opportunities and challenges of developing peptide drugs in the pharmaceutical industry. Peptides for Youth, Springer, pp 467–469Google Scholar
  45. Datki Z, Papp R, Zádori D, Soós K, Fülöp L, Juhász A, Laskay G, Hetényi C, Mihalik E, Zarándi M (2004) In vitro model of neurotoxicity of Aβ 1–42 and neuroprotection by a pentapeptide: irreversible events during the first hour. Neurobiol Dis 17(3):507–515PubMedGoogle Scholar
  46. Deane R, Bell RD, Sagare A, Zlokovic BV (2009) Clearance of amyloid-β peptide across the blood-brain barrier: implication for therapies in Alzheimers Disease. CNS Neurol Disord-Dr Targets 8:16. Google Scholar
  47. Deane R, Du Yan S, Submamaryan RK, LaRue B, Jovanovic S, Hogg E, Welch D, Manness L, Lin C, Yu J (2003) RAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brain. Nat Med 9(7):907PubMedGoogle Scholar
  48. Di Fede G, Catania M, Morbin M, Rossi G, Suardi S, Mazzoleni G, Merlin M, Giovagnoli AR, Prioni S, Erbetta A (2009) A recessive mutation in the APP gene with dominant-negative effect on amyloidogenesis. Science 323(5920):1473–1477PubMedPubMedCentralGoogle Scholar
  49. Dodel R, Du Y, Depboylu C, Hampel H, Frölich L, Haag A, Hemmeter U, Paulsen S, Teipel S, Brettschneider S (2004) Intravenous immunoglobulins containing antibodies against β-amyloid for the treatment of Alzheimer’s disease. J Neurol Neurosurg Psychiatry 75(10):1472–1474PubMedPubMedCentralGoogle Scholar
  50. Dong M, Li H, Hu D, Zhao W, Zhu X, Ai H (2016) Molecular dynamics study on the inhibition mechanisms of drugs CQ1–3 for Alzheimer amyloid-β40 aggregation induced by Cu2+. ACS Chem Neurosci 7(5):599–614PubMedGoogle Scholar
  51. Du Y, Wei X, Dodel R, Sommer N, Hampel H, Gao F, Ma Z, Zhao L, Oertel WH, Farlow M (2003) Human anti-β-amyloid antibodies block β-amyloid fibril formation and prevent β-amyloid-induced neurotoxicity. Brain 126(9):1935–1939PubMedGoogle Scholar
  52. Elbassal EA, Morris C, Kent TW, Lantz R, Ojha B, Wojcikiewicz EP, Du D (2017) Gold nanoparticles as a probe for amyloid-β oligomer and amyloid formation. J Phys Chem C 121(36):20007–20015Google Scholar
  53. Emi M, Wu LL, Robertson MA, Myers RL, Hegele RA, Williams RR, White R, Lalouel J-M (1988) Genotyping and sequence analysis of apolipoprotein E isoforms. Genomics 3(4):373–379PubMedGoogle Scholar
  54. Eskici G, Gur M (2013) Computational design of new peptide inhibitors for amyloid beta (Aβ) aggregation in Alzheimer’s disease: application of a novel methodology. PLoS One 8(6):e66178PubMedPubMedCentralGoogle Scholar
  55. Finder VH, Glockshuber R (2007) Amyloid-β aggregation. Neurodegener Dis 4(1):13–27PubMedGoogle Scholar
  56. Fradinger EA, Monien BH, Urbanc B, Lomakin A, Tan M, Li H, Spring SM, Condron MM, Cruz L, Xie C-W (2008) C-terminal peptides coassemble into Aβ42 oligomers and protect neurons against Aβ42-induced neurotoxicity. Proc Natl Acad Sci 105(37):14175–14180PubMedGoogle Scholar
  57. Friedemann M, Helk E, Tiiman A, Zovo K, Palumaa P, Tõugu V (2015) Effect of methionine-35 oxidation on the aggregation of amyloid-β peptide. Biochem Biophys Rep 3:94–99PubMedPubMedCentralGoogle Scholar
  58. Fu Z, Luo Y, Derreumaux P, Wei G (2009) Induced β-barrel formation of the Alzheimer’s Aβ25–35 oligomers on carbon nanotube surfaces: implication for amyloid fibril inhibition. Biophys J 97(6):1795–1803PubMedPubMedCentralGoogle Scholar
  59. Gao G, Zhang M, Gong D, Chen R, Hu X, Sun T (2017) The size-effect of gold nanoparticles and nanoclusters in the inhibition of amyloid-β fibrillation. Nanoscale 9(12):4107–4113PubMedGoogle Scholar
  60. 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(21):9146–9155PubMedGoogle Scholar
  61. Ghanta J, Shen C-L, Kiessling LL, Murphy RM (1996) A strategy for designing inhibitors of β-amyloid toxicity. J Biol Chem 271(47):29525–29528PubMedGoogle Scholar
  62. Giedraitis V, Sundelöf J, Irizarry MC, Gårevik N, Hyman BT, Wahlund L-O, Ingelsson M, Lannfelt L (2007) The normal equilibrium between CSF and plasma amyloid beta levels is disrupted in Alzheimer’s disease. Neurosci Lett 427(3):127–131PubMedGoogle Scholar
  63. Gillam J, MacPhee C (2013) Modelling amyloid fibril formation kinetics: mechanisms of nucleation and growth. J Phys Condens Matter 25(37):373101PubMedGoogle Scholar
  64. Glabe CC (2005) Amyloid accumulation and pathogenesis of Alzheimer’s disease: significance of monomeric, oligomeric and fibrillar Aβ. Alzheimer’s Disease, Springer, pp 167–177Google Scholar
  65. Gordon DJ, Sciarretta KL, Meredith SC (2001) Inhibition of β-amyloid (40) fibrillogenesis and disassembly of β-amyloid (40) fibrils by short β-amyloid congeners containing N-methyl amino acids at alternate residues. Biochemistry 40(28):8237–8245PubMedGoogle Scholar
  66. Goyal D, Shuaib S, Mann S, Goyal B (2017) Rationally designed peptides and peptidomimetics as inhibitors of amyloid-β (Aβ) aggregation: potential therapeutics of Alzheimer’s disease. ACS Comb Sci 19(2):55–80PubMedGoogle Scholar
  67. Graeber M, Kösel S, Egensperger R, Banati R, Müller U, Bise K, Hoff P, Möller H, Fujisawa K, Mehraein P (1997) Rediscovery of the case described by Alois Alzheimer in 1911: historical, histological and molecular genetic analysis. Neurogenetics 1(1):73–80PubMedGoogle Scholar
  68. Granic I, Masman MF, Nijholt IM, Naude PJ, de Haan A, Borbély E, Penke B, Luiten PG, Eisel UL (2010) LPYFDa neutralizes amyloid-β-induced memory impairment and toxicity. J Alzheimers Dis 19(3):991–1005PubMedGoogle Scholar
  69. Guo J, Sun W, Liu F (2017) Brazilin inhibits the Zn2+-mediated aggregation of amyloid β-protein and alleviates cytotoxicity. J Inorg Biochem 177:183–189PubMedGoogle Scholar
  70. Haass C, Selkoe DJ (1993) Cellular processing of β-amyloid precursor protein and the genesis of amyloid β-peptide. Cell 75(6):1039–1042PubMedGoogle Scholar
  71. Habchi J, Arosio P, Perni M, Costa AR, Yagi-Utsumi M, Joshi P, Chia S, Cohen SI, Müller MB, Linse S (2016) An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Aβ42 aggregates linked with Alzheimer’s disease. Sci Adv 2(2):e1501244PubMedPubMedCentralGoogle Scholar
  72. Hajipour MJ, Santoso MR, Rezaee F, Aghaverdi H, Mahmoudi M, Perry G (2017) Advances in Alzheimer’s diagnosis and therapy: the implications of nanotechnology. Trends Biotechnol 35(10):937–953PubMedGoogle Scholar
  73. Hall D, Edskes H (2012) Computational modeling of the relationship between amyloid and disease. Biophys Rev 4(3):205–222PubMedPubMedCentralGoogle Scholar
  74. Hall D, Edskes H (2009) A model of amyloid’s role in disease based on fibril fracture. Biophys Chem 145(1):17–28PubMedPubMedCentralGoogle Scholar
  75. Han F, Wang W, Chen C (2015) Research progress in animal models and stem cell therapy for Alzheimer’s disease. J Neuro-Oncol 3:11–22Google Scholar
  76. Han X, He G (2018) Toward a rational design to regulate β-amyloid fibrillation for Alzheimer’s disease treatment. ACS Chem Neurosci 9(2):198–210PubMedGoogle Scholar
  77. Handattu SP, Garber DW, Monroe CE, van Groen T, Kadish I, Nayyar G, Cao D, Palgunachari MN, Li L, Anantharamaiah G (2009) Oral apolipoprotein AI mimetic peptide improves cognitive function and reduces amyloid burden in a mouse model of Alzheimer’s disease. Neurobiol Dis 34(3):525–534PubMedPubMedCentralGoogle Scholar
  78. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297(5580):353–356PubMedGoogle Scholar
  79. Henke H, Lang W (1983) Cholinergic enzymes in neocortex, hippocampus and basal forebrain of non-neurological and senile dementia of Alzheimer-type patients. Brain Res 267(2):281–291PubMedGoogle Scholar
  80. Hochdörffer K, März-Berberich J, Nagel-Steger L, Epple M, Meyer-Zaika W, Horn AH, Sticht H, Sinha S, Bitan G, Schrader T (2011) Rational design of β-sheet ligands against Aβ42-induced toxicity. J Am Chem Soc 133(12):4348–4358PubMedGoogle Scholar
  81. Hu X, Zhang Q, Wang W, Yuan Z, Zhu X, Chen B, Chen X (2016) Tripeptide GGH as the inhibitor of copper-amyloid-β-mediated redox reaction and toxicity. ACS Chem Neurosci 7(9):1255–1263PubMedGoogle Scholar
  82. Ignatius MJ, Gebicke-Härter PJ, Skene J, Schilling JW, Weisgraber KH, Mahley RW, Shooter EM (1986) Expression of apolipoprotein E during nerve degeneration and regeneration. Proc Natl Acad Sci 83(4):1125–1129PubMedGoogle Scholar
  83. Ikeda K, Okada T, Sawada S-i, Akiyoshi K, Matsuzaki K (2006) Inhibition of the formation of amyloid β-protein fibrils using biocompatible nanogels as artificial chaperones. FEBS Lett 580(28-29):6587–6595PubMedGoogle Scholar
  84. Jagota S, Rajadas J (2013) Synthesis of d-amino acid peptides and their effect on beta-amyloid aggregation and toxicity in transgenic Caenorhabditis elegans. Med Chem Res 22(8):3991–4000Google Scholar
  85. Jaruszewski KM, Omtri RS, Kandimalla KK (2012) Role of nanotechnology in the diagnosis and treatment of Alzheimer’s. Curr Adv Med Appl Nanotechnol 107Google Scholar
  86. Jayasena T, Poljak A, Smythe G, Braidy N, Muench G, Sachdev P (2013) The role of polyphenols in the modulation of sirtuins and other pathways involved in Alzheimer’s disease. Ageing Res Rev 12(4):867–883PubMedGoogle Scholar
  87. Ji Y, Lee HJ, Kim M, Nam G, Lee SJC, Cho J, Park C-M, Lim MH (2017) Strategic design of 2, 2′-bipyridine derivatives to modulate metal–amyloid-β aggregation. Inorg Chem 56(11):6695–6705PubMedGoogle Scholar
  88. Jiang Z, Dong X, Liu H, Wang Y, Zhang L, Sun Y (2016) Multifunctionality of self-assembled nanogels of curcumin-hyaluronic acid conjugates on inhibiting amyloid β-protein fibrillation and cytotoxicity. React Funct Polym 104:22–29Google Scholar
  89. Jiang Z, Dong X, Sun Y (2018) Charge effects of self-assembled chitosan-hyaluronic acid nanoparticles on inhibiting amyloid β-protein aggregation. Carbohydr Res 461:11–18PubMedGoogle Scholar
  90. John T, Gladytz A, Kubeil C, Martin LL, Risselada HJ, Abel B (2018) Impact of nanoparticles on amyloid peptide and protein aggregation: a review with a focus on gold nanoparticles. Nanoscale 10(45):20894–20913Google Scholar
  91. Joshi SA, Chavhan SS, Sawant KK (2010) Rivastigmine-loaded PLGA and PBCA nanoparticles: preparation, optimization, characterization, in vitro and pharmacodynamic studies. Eur J Pharm Biopharm 76(2):189–199PubMedGoogle Scholar
  92. Kawashima H, Sohma Y, Nakanishi T, Kitamura H, Mukai H, Yamashita M, Akaji K, Kiso Y (2013) A new class of aggregation inhibitor of amyloid-β peptide based on an O-acyl isopeptide. Bioorg Med Chem 21(21):6323–6327PubMedGoogle Scholar
  93. Kino R, Araya T, Arai T, Sohma Y, Kanai M (2015) Covalent modifier-type aggregation inhibitor of amyloid-β based on a cyclo-KLVFF motif. Bioorg Med Chem Lett 25(15):2972–2975PubMedGoogle Scholar
  94. Klein AN, Ziehm T, Tusche M, Buitenhuis J, Bartnik D, Boeddrich A, Wiglenda T, Wanker E, Funke SA, Brener O (2016) Optimization of the all-D peptide D3 for Aβ oligomer elimination. PLoS One 11(4):e0153035PubMedPubMedCentralGoogle Scholar
  95. Knopman DS (2016) Alzheimer disease: preclinical Alzheimer disease—the new frontier. Nat Rev Neurol 12(11):620PubMedGoogle Scholar
  96. Kogan MJ, Bastus NG, Amigo R, Grillo-Bosch D, Araya E, Turiel A, Labarta A, Giralt E, Puntes VF (2006) Nanoparticle-mediated local and remote manipulation of protein aggregation. Nano Lett 6(1):110–115PubMedGoogle Scholar
  97. Kokkoni N, Stott K, Amijee H, Mason JM, Doig AJ (2006) N-Methylated peptide inhibitors of β-amyloid aggregation and toxicity. Optimization of the inhibitor structure. Biochemistry 45(32):9906–9918PubMedGoogle Scholar
  98. Kumaraswamy P, Sethuraman S, Krishnan UM (2012) Liposomal delivery of a beta sheet blocker peptide for the treatment of Alzheimer’s disease. Alzheimer’s Dement: J Alzheimer’s Assoc 8(4):P705Google Scholar
  99. Laganowsky A, Liu C, Sawaya MR, Whitelegge JP, Park J, Zhao M, Pensalfini A, Soriaga AB, Landau M, Teng PK (2012) Atomic view of a toxic amyloid small oligomer. Science 335(6073):1228–1231PubMedPubMedCentralGoogle Scholar
  100. Larbanoix L, Burtea C, Ansciaux E, Laurent S, Mahieu I, Vander Elst L, Muller RN (2011) Design and evaluation of a 6-mer amyloid-beta protein derived phage display library for molecular targeting of amyloid plaques in Alzheimer’s disease: comparison with two cyclic heptapeptides derived from a randomized phage display library. Peptides 32(6):1232–1243PubMedGoogle Scholar
  101. Leithold LH, Jiang N, Post J, Niemietz N, Schartmann E, Ziehm T, Kutzsche J, Shah NJ, Breitkreutz J, Langen K-J (2016) Pharmacokinetic properties of tandem d-peptides designed for treatment of Alzheimer’s disease. Eur J Pharm Sci 89:31–38PubMedGoogle Scholar
  102. Lemkul JA, Bevan DR (2012) The role of molecular simulations in the development of inhibitors of amyloid β-peptide aggregation for the treatment of Alzheimer’s disease. ACS Chem Neurosci 3(11):845–856PubMedPubMedCentralGoogle Scholar
  103. Li H, Du Z, Lopes DH, Fradinger EA, Wang C, Bitan G (2011a) C-terminal tetrapeptides inhibit Aβ42-induced neurotoxicity primarily through specific interaction at the N-terminus of Aβ42. J Med Chem 54(24):8451–8460PubMedPubMedCentralGoogle Scholar
  104. Li H, Luo Y, Derreumaux P, Wei G (2011b) Carbon nanotube inhibits the formation of β-sheet-rich oligomers of the Alzheimer’s amyloid-β (16-22) peptide. Biophys J 101(9):2267–2276PubMedPubMedCentralGoogle Scholar
  105. Li M, Guan Y, Ding C, Chen Z, Ren J, Qu X (2016) An ultrathin graphitic carbon nitride nanosheet: a novel inhibitor of metal-induced amyloid aggregation associated with Alzheimer’s disease. J Mater Chem B 4(23):4072–4075Google Scholar
  106. Li X, Xie B, Dong X, Sun Y (2018) Bifunctionality of iminodiacetic acid-modified lysozyme on inhibiting Zn2+-mediated amyloid β-protein aggregation. Langmuir 34(17):5106–5115PubMedGoogle Scholar
  107. Liao YH, Chang YJ, Yoshiike Y, Chang YC, Chen YR (2012) Negatively charged gold nanoparticles inhibit Alzheimer’s amyloid-β fibrillization, induce fibril dissociation, and mitigate neurotoxicity. Small 8(23):3631–3639PubMedGoogle Scholar
  108. Liu, F., W. Wang, J. Sang, L. Jia and F. Lu (2018). Hydroxylated single-walled carbon nanotubes inhibit Aβ42 fibrillogenesis, disaggregate mature fibrils, and protect against Aβ42-induced cytotoxicity. ACS Chem NeurosciGoogle Scholar
  109. Liu G, Men P, Harris PL, Rolston RK, Perry G, Smith MA (2006) Nanoparticle iron chelators: a new therapeutic approach in Alzheimer disease and other neurologic disorders associated with trace metal imbalance. Neurosci Lett 406(3):189–193PubMedGoogle Scholar
  110. Liu H, Dong X, Liu F, Zheng J, Sun Y (2017a) Iminodiacetic acid-conjugated nanoparticles as a bifunctional modulator against Zn2+-mediated amyloid β-protein aggregation and cytotoxicity. J Colloid Interface Sci 505:973–982PubMedGoogle Scholar
  111. Liu H, Xie B, Dong X, Zhang L, Wang Y, Liu F, Sun Y (2016) Negatively charged hydrophobic nanoparticles inhibit amyloid β-protein fibrillation: the presence of an optimal charge density. React Funct Polym 103:108–116Google Scholar
  112. Liu H, Yu L, Dong X, Sun Y (2017b) Synergistic effects of negatively charged hydrophobic nanoparticles and (−)-epigallocatechin-3-gallate on inhibiting amyloid β-protein aggregation. J Colloid Interface Sci 491:305–312PubMedGoogle Scholar
  113. Liu J, Wang W, Zhang Q, Zhang S, Yuan Z (2014) Study on the efficiency and interaction mechanism of a decapeptide inhibitor of β-amyloid aggregation. Biomacromolecules 15(3):931–939PubMedGoogle Scholar
  114. Liu S, Zhao J, Li K, Wan K, Sun T, Zheng N, Zhu F, Ma J, Jiao J, Li T, Ni J (2019a) Organoplatinum-substituted polyoxometalate inhibits β-amyloid aggregation for Alzheimer’s therapy. Angew ChemGoogle Scholar
  115. Liu, W., X. Dong and Y. Sun (2019b). D-Enantiomeric RTHLVFFARK-NH2: a potent multifunctional decapeptide inhibiting Cu2+-mediated amyloid β-protein aggregation and remodeling Cu2+-mediated amyloid β aggregates. ACS Chem NeurosciGoogle Scholar
  116. Liu Z, Li X, Wu X, Zhu C (2019c) A dual-inhibitor system for the effective antifibrillation of Aβ40 peptides by biodegradable EGCG–Fe (iii)/PVP nanoparticles. J Mater Chem B 7(8):1292–1299Google Scholar
  117. Lott IT, Dierssen M (2010) Cognitive deficits and associated neurological complications in individuals with Down’s syndrome. Lancet Neurol 9(6):623–633PubMedGoogle Scholar
  118. Loureiro JA, Crespo R, Börner H, Martins PM, Rocha FA, Coelho M, Pereira MC, Rocha S (2014) Fluorinated beta-sheet breaker peptides. J Mater Chem B 2(16):2259–2264Google Scholar
  119. Luheshi LM, Hoyer W, de Barros TP, van Dijk Härd I, Brorsson A-C, Macao B, Persson C, Crowther DC, Lomas DA, Ståhl S (2010) Sequestration of the Aβ peptide prevents toxicity and promotes degradation in vivo. PLoS Biol 8(3):e1000334PubMedPubMedCentralGoogle Scholar
  120. Lührs T, Ritter C, Adrian M, Riek-Loher D, Bohrmann B, Döbeli H, Schubert D, Riek R (2005) 3D structure of Alzheimer’s amyloid-β (1–42) fibrils. Proc Natl Acad Sci 102(48):17342–17347PubMedGoogle Scholar
  121. Luo J, Abrahams JP (2014) Cyclic peptides as inhibitors of amyloid fibrillation. Chem Eur J 20(9):2410–2419PubMedGoogle Scholar
  122. Mahmoudi M, Akhavan O, Ghavami M, Rezaee F, Ghiasi SMA (2012) Graphene oxide strongly inhibits amyloid beta fibrillation. Nanoscale 4(23):7322–7325PubMedGoogle Scholar
  123. Mandel S, Amit T, Bar-Am O, Youdim MB (2007) Iron dysregulation in Alzheimer’s disease: multimodal brain permeable iron chelating drugs, possessing neuroprotective-neurorescue and amyloid precursor protein-processing regulatory activities as therapeutic agents. Prog Neurobiol 82(6):348–360PubMedGoogle Scholar
  124. Mandelkow E-M, Mandelkow E (1998) Tau in Alzheimer’s disease. Trends Cell Biol 8(11):425–427PubMedGoogle Scholar
  125. Marambaud P, Zhao H, Davies P (2005) Resveratrol promotes clearance of Alzheimer’s disease amyloid-β peptides. J Biol Chem 280(45):37377–37382PubMedGoogle Scholar
  126. Martin TD, Malagodi AJ, Chi EY, Evans DG (2018) Computational study of the driving forces and dynamics of curcumin binding to amyloid-β protofibrils. J Phys Chem B 123(3):551–560Google Scholar
  127. Martínez A, Alcendor R, Rahman T, Podgorny M, Sanogo I, McCurdy R (2016) Ionophoric polyphenols selectively bind Cu2+, display potent antioxidant and anti-amyloidogenic properties, and are non-toxic toward Tetrahymena thermophila. Bioorg Med Chem 24(16):3657–3670PubMedGoogle Scholar
  128. Matsuoka Y, Jouroukhin Y, Gray AJ, Ma L, Hirata-Fukae C, Li H-F, Feng L, Lecanu L, Walker BR, Planel E (2008) A neuronal microtubule-interacting agent, NAPVSIPQ, reduces tau pathology and enhances cognitive function in a mouse model of Alzheimer’s disease. J Pharmacol Exp Ther 325(1):146–153PubMedGoogle Scholar
  129. Mattson MP (2004) Pathways towards and away from Alzheimer’s disease. Nature 430(7000):631PubMedPubMedCentralGoogle Scholar
  130. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group* under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34(7):939–939PubMedGoogle Scholar
  131. Mehrazma B, Opare S, Petoyan A, Rauk A (2018) D-Amino acid pseudopeptides as potential amyloid-beta aggregation inhibitors. Molecules 23(9):2387PubMedCentralGoogle Scholar
  132. Mehta, M., A. Adem and M. Sabbagh (2012) New acetylcholinesterase inhibitors for Alzheimer’s disease. Int J Alzheimers DisGoogle Scholar
  133. Meng J, Zhang H, Dong X, Liu F, Sun Y (2018) RTHLVFFARK-NH2: a potent and selective modulator on Cu2+-mediated amyloid-β protein aggregation and cytotoxicity. J Inorg Biochem 181:56–64PubMedGoogle Scholar
  134. Minicozzi V, Chiaraluce R, Consalvi V, Giordano C, Narcisi C, Punzi P, Rossi GC, Morante S (2014) Computational and experimental studies on β-sheet breakers targeting Aβ1–40 fibrils. J Biol Chem 289(16):11242–11252PubMedPubMedCentralGoogle Scholar
  135. Moore KA, Pate KM, Soto-Ortega DD, Lohse S, van der Munnik N, Lim M, Jackson KS, Lyles VD, Jones L, Glassgow N (2017) Influence of gold nanoparticle surface chemistry and diameter upon Alzheimer’s disease amyloid-β protein aggregation. J Biol Eng 11(1):5PubMedPubMedCentralGoogle Scholar
  136. 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(14):10311–10324PubMedGoogle Scholar
  137. Nie Q, Du X-g, Geng M-y (2011) Small molecule inhibitors of amyloid β peptide aggregation as a potential therapeutic strategy for Alzheimer’s disease. Acta Pharmacol Sin 32(5):545PubMedPubMedCentralGoogle Scholar
  138. Ono K, Hasegawa K, Naiki H, Yamada M (2004) Curcumin has potent anti-amyloidogenic effects for Alzheimer’s β-amyloid fibrils in vitro. J Neurosci Res 75(6):742–750PubMedGoogle Scholar
  139. Oliveri V, Francesco B, Graziella V (2017) Structural isomers of cyclodextrin-bearing IOX1 compound as inhibitors of Aβ aggregation. Chem Select 2(2):655–659Google Scholar
  140. Pansieri J, Gerstenmayer M, Lux F, Mériaux S, Tillement O, Forge V, Larrat B, Marquette C (2018) Magnetic nanoparticles applications for amyloidosis study and detection: a review. Nanomaterials 8(9):740PubMedCentralGoogle Scholar
  141. Parthsarathy V, McClean PL, Hölscher C, Taylor M, Tinker C, Jones G, Kolosov O, Salvati E, Gregori M, Masserini M (2013) A novel retro-inverso peptide inhibitor reduces amyloid deposition, oxidation and inflammation and stimulates neurogenesis in the APPswe/PS1ΔE9 mouse model of Alzheimer’s disease. PLoS One 8(1):e54769PubMedPubMedCentralGoogle Scholar
  142. Pedersen JT, Borg CB, Michaels TC, Knowles TP, Faller P, Teilum K, Hemmingsen L (2015) Aggregation-prone amyloid-β· CuII species formed on the millisecond timescale under mildly acidic conditions. ChemBioChem 16(9):1293–1297PubMedGoogle Scholar
  143. Petkova AT, Ishii Y, Balbach JJ, Antzutkin ON, Leapman RD, Delaglio F, Tycko R (2002) A structural model for Alzheimer’s β-amyloid fibrils based on experimental constraints from solid state NMR. Proc Natl Acad Sci 99(26):16742–16747PubMedGoogle Scholar
  144. Podolski IY, Podlubnaya Z, Kosenko E, Mugantseva E, Makarova E, Marsagishvili L, Shpagina M, Kaminsky YG, Andrievsky G, Klochkov V (2007) Effects of hydrated forms of C60 fullerene on amyloid β-peptide fibrillization in vitro and performance of the cognitive task. J Nanosci Nanotechnol 7(4-5):1479–1485PubMedGoogle Scholar
  145. 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(1):27–37PubMedGoogle Scholar
  146. Prince, MJ (2015) World Alzheimer Report 2015: the global impact of dementia: an analysis of prevalence, incidence, cost and trends. Alzheimer's Disease International 2015.
  147. Prince M, Comas-Herrera A, Knapp M, Guerchet M and Karagiannidou M (2016). World Alzheimer report 2016: improving healthcare for people living with dementia: coverage, quality and costs now and in the futureGoogle Scholar
  148. Ramaswamy K, Kumaraswamy P, Sethuraman S, Krishnan UM (2014) Self-assembly characteristics of a structural analogue of Tjernberg peptide. RSC Adv 4(32):16517–16523Google Scholar
  149. Rana M, Cho H-J, Roy TK, Mirica LM, Sharma AK (2018) Azo-dyes based small bifunctional molecules for metal chelation and controlling amyloid formation. Inorg Chim Acta 471:419–429Google Scholar
  150. Rao PP, Mohamed T, Teckwani K, Tin G (2015) Curcumin binding to beta amyloid: a computational study. Chem Biol Drug Des 86(4):813–820PubMedGoogle Scholar
  151. Reddy G, Straub JE, Thirumalai D (2009) Influence of preformed asp23− lys28 salt bridge on the conformational fluctuations of monomers and dimers of Aβ peptides with implications for rates of fibril formation. J Phys Chem B 113(4):1162–1172PubMedPubMedCentralGoogle Scholar
  152. Reiman EM (2016) Alzheimer’s disease: attack on amyloid-β protein. Nature 537(7618):36PubMedPubMedCentralGoogle Scholar
  153. Reinke AA, Gestwicki JE (2007) Structure–activity relationships of amyloid beta-aggregation inhibitors based on curcumin: influence of linker length and flexibility. Chem Biol Drug Des 70(3):206–215PubMedGoogle Scholar
  154. Ren B, Jiang B, Hu R, Zhang M, Chen H, Ma J, Sun Y, Jia L, Zheng J (2016) HP-β-cyclodextrin as an inhibitor of amyloid-β aggregation and toxicity. Phys Chem Chem Phys 18(30):20476–20485PubMedGoogle Scholar
  155. Ren B, Zhang M, Hu R, Chen H, Wang M, Lin Y, Sun Y, Jia L, Liang G, Zheng J (2017) Identification of a new function of cardiovascular disease drug 3-morpholinosydnonimine hydrochloride as an amyloid-β aggregation inhibitor. ACS Omega 2(1):243–250PubMedPubMedCentralGoogle Scholar
  156. Rezai-Zadeh K, Shytle D, Sun N, Mori T, Hou H, Jeanniton D, Ehrhart J, Townsend K, Zeng J, Morgan D (2005) Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice. J Neurosci 25(38):8807–8814PubMedPubMedCentralGoogle Scholar
  157. Richman M, Wilk S, Chemerovski M, Wärmländer SK, Wahlström A, Gräslund A, Rahimipour S (2013) In vitro and mechanistic studies of an antiamyloidogenic self-assembled cyclic d, l-α-peptide architecture. J Am Chem Soc 135(9):3474–3484PubMedGoogle Scholar
  158. Rigacci S, Guidotti V, Bucciantini M, Nichino D, Relini A, Berti A, Stefani M (2011) Aβ (1-42) aggregates into non-toxic amyloid assemblies in the presence of the natural polyphenol oleuropein aglycon. Curr Alzheimer Res 8(8):841–852PubMedGoogle Scholar
  159. Ringman JM, Frautschy SA, Teng E, Begum AN, Bardens J, Beigi M, Gylys KH, Badmaev V, Heath DD, Apostolova LG (2012) Oral curcumin for Alzheimer’s disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study. Alzheimers Res Ther 4(5):43PubMedPubMedCentralGoogle Scholar
  160. Ritchie CW, Bush AI, Mackinnon A, Macfarlane S, Mastwyk M, MacGregor L, Kiers L, Cherny R, Li Q-X, Tammer A (2003) Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Aβ amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol 60(12):1685–1691PubMedGoogle Scholar
  161. Rossor M, Emson P, Mountjoy C, Roth M, Iversen L (1980) Reduced amounts of immunoreactive somatostatin in the temporal cortex in senile dementia of Alzheimer type. Neurosci Lett 20(3):373–377PubMedGoogle Scholar
  162. Rossor M, Revesz T, Lantos P, Warrington EK (2000) Semantic dementia with ubiquitin-positive tau-negative inclusion bodies. Brain 123(2):267–276PubMedGoogle Scholar
  163. Sahni JK, Doggui S, Ali J, Baboota S, Dao L, Ramassamy C (2011) Neurotherapeutic applications of nanoparticles in Alzheimer’s disease. J Control Release 152(2):208–231PubMedGoogle Scholar
  164. Salvati A, Pitek AS, Monopoli MP, Prapainop K, Bombelli FB, Hristov DR, Kelly PM, Åberg C, Mahon E, Dawson KA (2013) Transferrin-functionalized nanoparticles lose their targeting capabilities when a biomolecule corona adsorbs on the surface. Nat Nanotechnol 8(2):137PubMedGoogle Scholar
  165. Sastre M, Ritchie CW, Hajji N (2015) Metal ions in Alzheimer’s disease brain. JSM Alzheimer’s Dis Relat Dement 2:1014Google Scholar
  166. Savelieff MG, Nam G, Kang J, Lee HJ, Lee M, Lim MH (2018) Development of multifunctional molecules as potential therapeutic candidates for Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis in the last decade. Chem Rev 119(2):1221–1322PubMedGoogle Scholar
  167. Scherzer-Attali R, Pellarin R, Convertino M, Frydman-Marom A, Egoz-Matia N, Peled S, Levy-Sakin M, Shalev DE, Caflisch A, Gazit E (2010) Complete phenotypic recovery of an Alzheimer’s disease model by a quinone-tryptophan hybrid aggregation inhibitor. PLoS One 5(6):e11101PubMedPubMedCentralGoogle Scholar
  168. Schöneich C, Williams TD (2002) Cu (II)-catalyzed oxidation of β-amyloid peptide targets His13 and His14 over His6: detection of 2-Oxo-histidine by HPLC-MS/MS. Chem Res Toxicol 15(5):717–722PubMedGoogle Scholar
  169. Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81(2):741–766PubMedGoogle Scholar
  170. Shamloo A, Asadbegi M, Khandan V, Amanzadi A (2018) Designing a new multifunctional peptide for metal chelation and Aβ inhibition. Arch Biochem Biophys 653:1–9PubMedGoogle Scholar
  171. Sharma S, Nehru B, Saini A (2017) Inhibition of Alzheimer’s amyloid-beta aggregation in-vitro by carbenoxolone: insight into mechanism of action. Neurochem Int 108:481–493PubMedGoogle Scholar
  172. Shuaib S, Goyal B (2018) Scrutiny of the mechanism of small molecule inhibitor preventing conformational transition of amyloid-β42 monomer: insights from molecular dynamics simulations. J Biomol Struct Dyn 36(3):663–678PubMedGoogle Scholar
  173. Singer O, Marr RA, Rockenstein E, Crews L, Coufal NG, Gage FH, Verma IM, Masliah E (2005) Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model. Nat Neurosci 8(10):1343PubMedGoogle Scholar
  174. Sloane PD, Zimmerman S, Suchindran C, Reed P, Wang L, Boustani M, Sudha S (2002) The public health impact of Alzheimer’s disease, 2000–2050: potential implication of treatment advances. Annu Rev Public Health 23Google Scholar
  175. Sohma Y (2016) Medicinal chemistry focusing on aggregation of amyloid-β. Chem Pharm Bull 64(1):1–7PubMedGoogle Scholar
  176. Soininen H, Kosunen O, Helisalmi S, Mannermaa A, Paljärvi L, Talasniemi S, Ryynänen M, Riekkinen P Sr (1995) A severe loss of choline acetyltransferase in the frontal cortex of Alzheimer patients carrying apolipoprotein ε4 allele. Neurosci Lett 187(2):79–82PubMedGoogle Scholar
  177. Soltani N, Gholami MR (2017) Increase in the β-sheet character of an amyloidogenic peptide upon adsorption onto gold and silver surfaces. ChemPhysChem 18(5):526–536PubMedGoogle Scholar
  178. Sood S, Jain K, Gowthamarajan K (2014) Intranasal therapeutic strategies for management of Alzheimer’s disease. J Drug Target 22(4):279–294PubMedGoogle Scholar
  179. Soto C, Kindy MS, Baumann M, Frangione B (1996) Inhibition of Alzheimer’s amyloidosis by peptides that prevent β-sheet conformation. Biochem Biophys Res Commun 226(3):672–680PubMedGoogle Scholar
  180. Soto C, Sigurdsson EM, Morelli L, Kumar RA, Castaño EM, Frangione B (1998) β-Sheet breaker peptides inhibit fibrillogenesis in a rat brain model of amyloidosis: implications for Alzheimer’s therapy. Nat Med 4(7):822–826PubMedGoogle Scholar
  181. Su T, Zhang T, Xie S, Yan J, Wu Y, Li X, Huang L, Luo H-B (2016) Discovery of novel PDE9 inhibitors capable of inhibiting Aβ aggregation as potential candidates for the treatment of Alzheimer’s disease. Sci Rep 6:21826PubMedPubMedCentralGoogle Scholar
  182. Sudhakar S, Kalipillai P, Santhosh PB, Mani E (2017) Role of surface charge of inhibitors on amyloid beta fibrillation. J Phys Chem C 121(11):6339–6348Google Scholar
  183. Sun N, Funke AS, Willbold D (2012) A survey of peptides with effective therapeutic potential in Alzheimer’s disease rodent models or in human clinical studies. Mini-Rev Med Chem 12(5):388–398PubMedPubMedCentralGoogle Scholar
  184. Tamaoka A, Sawamura N, Fukushima T, Shoji S, Matsubara E, Shoji M, Hirai S, Furiya Y, Endoh R, Mori H (1997) Amyloid β protein 42 (43) in cerebrospinal fluid of patients with Alzheimer’s disease. J Neurol Sci 148(1):41–45PubMedGoogle Scholar
  185. Taylor M, Moore S, Mayes J, Parkin E, Beeg M, Canovi M, Gobbi M, Mann DM, Allsop D (2010) Development of a proteolytically stable retro-inverso peptide inhibitor of β-amyloid oligomerization as a potential novel treatment for Alzheimer’s disease. Biochemistry 49(15):3261–3272PubMedGoogle Scholar
  186. Tjernberg LO, Näslund J, Lindqvist F, Johansson J, Karlström AR, Thyberg J, Terenius L, Nordstedt C (1996) Arrest of-amyloid fibril formation by a pentapeptide ligand. J Biol Chem 271(15):8545–8548PubMedGoogle Scholar
  187. Török M, Abid M, Mhadgut SC, Török B (2006) Organofluorine inhibitors of amyloid fibrillogenesis. Biochemistry 45(16):5377–5383PubMedGoogle Scholar
  188. Urbanc B, Cruz L, Yun S, Buldyrev SV, Bitan G, Teplow DB, Stanley HE (2004) In silico study of amyloid β-protein folding and oligomerization. Proc Natl Acad Sci 101(50):17345–17350PubMedGoogle Scholar
  189. Van Groen T, Wiesehan K, Funke SA, Kadish I, Nagel-Steger L, Willbold D (2008) Reduction of Alzheimer’s disease amyloid plaque load in transgenic mice by D3, ad-enantiomeric peptide identified by mirror image phage display. ChemMedChem: Chem Enabling Drug Discov 3(12):1848–1852Google Scholar
  190. Villari V, Tosto R, Di Natale G, Sinopoli A, Tomasello MF, Lazzaro S, Micali N, Pappalardo G (2017) A metalloporphyrin-peptide conjugate as an effective inhibitor of amyloid-β peptide fibrillation and cytotoxicity. ChemistrySelect 2(28):9122–9129Google Scholar
  191. Walsh DM, Selkoe DJ (2007) Aβ oligomers–a decade of discovery. J Neurochem 101(5):1172–1184PubMedGoogle Scholar
  192. Wang D, Zhang Q, Hu X, Wang W, Zhu X, Yuan Z (2018) Pharmacodynamics in Alzheimer’s disease model rats of a bifunctional peptide with the potential to accelerate the degradation and reduce the toxicity of amyloid β-Cu fibrils. Acta Biomater 65:327–338PubMedGoogle Scholar
  193. Wang L, Zeng R, Pang X, Gu Q, Tan W (2015) The mechanisms of flavonoids inhibiting conformational transition of amyloid-β 42 monomer: a comparative molecular dynamics simulation study. RSC Adv 5(81):66391–66402Google Scholar
  194. Wang W, Han Y, Fan Y, Wang Y (2019) Effects of gold nanospheres and nanocubes on amyloid-β peptide fibrillation. Langmuir.Google Scholar
  195. Wells JA, McClendon CL (2007) Reaching for high-hanging fruit in drug discovery at protein–protein interfaces. Nature 450(7172):1001PubMedGoogle Scholar
  196. Wiesehan K, Buder K, Linke RP, Patt S, Stoldt M, Unger E, Schmitt B, Bucci E, Willbold D (2003) Selection of D-amino-acid peptides that bind to Alzheimer’s disease amyloid peptide Aβ1–42 by mirror image phage display. Chembiochem 4(8):748–753PubMedGoogle Scholar
  197. Wimo A, Jönsson L, Bond J, Prince M, Winblad B, A. D. International (2013) The worldwide economic impact of dementia 2010. Alzheimers Dement 9(1):1–11. e13PubMedGoogle Scholar
  198. Wisniewski H, Wegiel J (1995) The neuropathology of Alzheimer’s disease. Neuroimaging Clin N Am 5(1):45–57PubMedGoogle Scholar
  199. Wood SJ, Wetzel R, Martin JD, Hurle MR (1995) Prolines and aamyloidogenicity in fragments of the Alzheimer’s peptide. beta./A4. Biochemistry 34(3):724–730PubMedGoogle Scholar
  200. Xiong N, Dong X-Y, Zheng J, Liu F-F, Sun Y (2015) Design of LVFFARK and LVFFARK-functionalized nanoparticles for inhibiting amyloid β-protein fibrillation and cytotoxicity. ACS Appl Mater Interfaces 7(10):5650–5662PubMedGoogle Scholar
  201. Xiong N, Zhao Y, Dong X, Zheng J, Sun Y (2017) Design of a molecular hybrid of dual peptide inhibitors coupled on AuNPs for enhanced inhibition of amyloid β-protein aggregation and cytotoxicity. Small 13(13):1601666Google Scholar
  202. Yan LM, Velkova A, Tatarek-Nossol M, Rammes G, Sibaev A, Andreetto E, Kracklauer M, Bakou M, Malideli E, Göke B (2013) Selectively N-methylated soluble IAPP mimics as potent IAPP receptor agonists and nanomolar inhibitors of cytotoxic self-assembly of both IAPP and Aβ40. Angew Chem Int Ed 52(39):10378–10383Google Scholar
  203. Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, Chen PP, Kayed R, Glabe CG, Frautschy SA (2005) Curcumin inhibits formation of amyloid β oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem 280(7):5892–5901PubMedGoogle Scholar
  204. Yang X, Cai P, Liu Q, Wu J, Yin Y, Wang X, Kong L (2018) Novel 8-hydroxyquinoline derivatives targeting β-amyloid aggregation, metal chelation and oxidative stress against Alzheimer’s disease. Bioorg Med Chem 26(12):3191–3201PubMedGoogle Scholar
  205. Yang Y, Chen T, Zhu S, Gu X, Jia X, Lu Y, Zhu L (2015) Two macrocyclic polyamines as modulators of metal-mediated Aβ40 aggregation. Integr Biol 7(6):655–662Google Scholar
  206. Yang W, Wong Y, Ng OT, Bai LP, Kwong DW, Ke Y, Jiang ZH, Li HW, Yung KK, Wong MS (2012) Inhibition of beta-amyloid peptide aggregation by multifunctional carbazole-based fluorophores. Angew Chem Int Ed 51(8):1804–1810Google Scholar
  207. Yoo SI, Yang M, Vivekanandan Subramanian D, Brender JR, Sun K, Joo NE, Jeong S-H, Ramamoorthy A, Kotov NA (2011) Mechanism of fibrillation inhibition of amyloid peptides by inorganic nanoparticles reveal functional similarities with proteins. Angew Chem Int Ed Eng 50(22):5110Google Scholar
  208. Zhang H, Dong X, Liu F, Zheng J, Sun Y (2018a) Ac-LVFFARK-NH2 conjugation to β-cyclodextrin exhibits significantly enhanced performance on inhibiting amyloid β-protein fibrillogenesis and cytotoxicity. Biophys Chem 235:40–47PubMedGoogle Scholar
  209. Zhang H, Dong X, Sun Y (2018b) Carnosine-LVFFARK-NH2 conjugate: a moderate chelator but potent inhibitor of Cu2+-mediated amyloid β-protein aggregation. ACS Chem Neurosci 9(11):2689–2700PubMedGoogle Scholar
  210. Zhang H, Zhang C, Dong XY, Zheng J, Sun Y (2018c) Design of nonapeptide LVFFARKHH: a bifunctional agent against Cu2+-mediated amyloid β-protein aggregation and cytotoxicity. J Mol Recognit 31(6):e2697PubMedGoogle Scholar
  211. Zhang J, Zhou X, Yu Q, Yang L, Sun D, Zhou Y, Liu J (2014) Epigallocatechin-3-gallate (EGCG)-stabilized selenium nanoparticles coated with Tet-1 peptide to reduce amyloid-β aggregation and cytotoxicity. ACS Appl Mater Interfaces 6(11):8475–8487PubMedGoogle Scholar
  212. Zhang Q, Hu X, Wang W, Yuan Z (2016) Study of a bifunctional Aβ aggregation inhibitor with the abilities of antiamyloid-β and copper chelation. Biomacromolecules 17(2):661–668PubMedGoogle Scholar
  213. Zhang Y x, Wang SW, Lu S, Zhang LX, Liu DQ, Ji M, Wang WY, Liu RT (2017) A mimotope of Aβ oligomers may also behave as a β-sheet inhibitor. FEBS Lett 591(21):3615–3624PubMedGoogle Scholar
  214. Zhao G, Dong X, Sun Y (2018) Self-assembled curcumin–poly (carboxybetaine methacrylate) conjugates: potent nano-inhibitors against amyloid β-protein fibrillogenesis and cytotoxicity. Langmuir.Google Scholar
  215. Zheng X, Wu C, Liu D, Li H, Bitan G, Shea J-E, Bowers MT (2015) Mechanism of C-terminal fragments of amyloid β-protein as Aβ inhibitors: do C-terminal interactions play a key role in their inhibitory activity? J Phys Chem B 120(8):1615–1623PubMedPubMedCentralGoogle Scholar
  216. Zhu L, Han Y, He C, Huang X, Wang Y (2014) Disaggregation ability of different chelating molecules on copper ion-triggered amyloid fibers. J Phys Chem B 118(31):9298–9305PubMedGoogle Scholar
  217. Zou Y, Qian Z, Chen Y, Qian H, Wei G, Zhang Q (2019) Norepinephrine inhibits Alzheimer’s amyloid-β peptide aggregation and destabilizes amyloid-β protofibrils: a molecular dynamics simulation study. ACS Chem NeurosciGoogle Scholar

Copyright information

© International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Nuclear Pharmacy, Faculty of PharmacyTehran University of Medical SciencesTehranIran
  2. 2.Department of Pharmaceutical Biomaterials , Faculty of PharmacyTehran University of Medical SciencesTehranIran
  3. 3.Department of Mechanical EngineeringSharif University of TechnologyTehranIran
  4. 4.Radiation Application Research SchoolNuclear Science and Technology Research Institute (NSTRI)TehranIran
  5. 5.Research Center for Nuclear MedicineTehran University of Medical SciencesTehranIran
  6. 6.Department of Mechanical and Aerospace EngineeringShiraz University of TechnologyShirazIran

Personalised recommendations