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Current Alzheimer Research


ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Review Article

Strategies Targeting Soluble β-Amyloid Oligomers and their Application to Early Diagnosis of Alzheimer’s Disease

Author(s): Fantian Zeng, Yuyan Li *, Yungen Xu, Jian Yang, Zhengshi Liu, Xiaofang Li and Longfei Ren

Volume 16, Issue 12, 2019

Page: [1132 - 1142] Pages: 11

DOI: 10.2174/1567205016666191031163504

Price: $65


Background: Alzheimer’s Disease (AD) is the most common neurodegenerative disorder, and it is still incurable. Early diagnosis and intervention are crucial for delaying the onset and progression of the disease. Mounting evidence indicates that the neurotoxic effects might be attributed to Soluble β-Amyloid Oligomers (SAβO). The SAβO are believed to be neurotoxic peptides more predominant than Aβ plaques in the early stage, and their key role in AD is self-evident. Unfortunately, identification of SAβO proves to be difficult due to their heterogeneous and transient nature. In spite of many obstacles, multiple techniques have recently been developed to target SAβO effectively. This review focuses on the recent progress in the approaches towards SAβO detection in order to shed some light on the future development of SAβO assays.

Methods: Literatures were obtained from the following libraries: Web of Science, PubMed, EPO, SIPO, USPTO. Articles were critically reviewed based on their titles, abstracts, and contents.

Results: A total of 85 papers are referenced in the review. Results are divided into three categories based on the types of detection methods: small molecule fluorescence probes, oligomer-specific antibodies and electrochemical biosensors. Finally, the improvements and challenges of these approaches applied in the early diagnosis of AD were discussed.

Conclusion: This review article covers three kinds of strategies that could be translated into clinic practice and lead to earlier diagnosis and therapeutic interventions of AD.

Keywords: Alzheimer's disease, antibodies, β-amyloid oligomers, electrochemical biosensors, early diagnosis, probes.

Chiti F, Dobson CM. Protein misfolding, functional amyloid, and human disease. Annu Rev Biochem 75(1): 333-66. (2006).
Pepys MB. Amyloidosis. Annu Rev Med 57(1): 223-41. (2006).
2018 Alzheimer’s disease facts and figures. Alzheimers Dement 14(3): 367-429. (2018).
Klimova B, Kuca K, Maresova P. Global view on Alzheimer’s disease and diabetes mellitus: threats, risks and treatment alzheimer’s disease and diabetes mellitus. Curr Alzheimer Res 15(14): 1277-82. (2018).
Hamley IW. The amyloid beta peptide: a chemist’s perspective. Role in Alzheimer’s and fibrillization. Chem Rev 112(10): 5147-92. (2012).
Matsuzono K, Hishikawa N, Ohta Y, Yamashita T, Deguchi K, Nakano Y, et al. Combination therapy of cholinesterase inhibitor (donepezil or galantamine) plus memantine in the okayama memantine study. J Alzheimers Dis 45(3): 771-80. (2015).
Salomone S, Caraci F, Leggio GM. New pharmacological strategies for treatment of Alzheimer’s disease: focus on disease modifying drugs. Br J Clin Pharmacol 7(4): 504-17. (2012).
Michela Rosini ES. Roberta Caporaso, Anna Minarini. Multitarget strategies in Alzheimer’s disease: benefts and challenges on the road to therapeutics. Future Med Chem 8: 679-711. (2016).
Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7(3): 280-92. (2011).
Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7(3): 270-9. (2011).
Guzman-Martinez L, Maccioni RB, Farias GA, Fuentes P, Navarrete LP. Biomarkers for Alzheimer’s Disease. Curr Alzheimer Res 16(6): 518-28. (2019).
Mazzon G, Ajcevic M, Cattaruzza T, Menichelli A, Guerriero M, Capitanio S, et al. Connected speech deficit as an early hallmark of csf-defined alzheimer’s disease and correlation with cerebral hypoperfusion pattern. Curr Alzheimer Res 16(6): 483-94. (2019).
Francois M, Bull CF, Fenech MF, Leifert WR. current state of saliva biomarkers for aging and Alzheimer’s disease. Curr Alzheimer Res 16(1): 56-66. (2019).
Blennow K, Hampel H, Weiner M, Zetterberg H. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol 6: 131. (2010).
Herholz K, Ebmeier K. Clinical amyloid imaging in Alzheimer’s disease. Lancet Neurol 10(7): 667-70. (2011).
Lu F-M, Yuan Z. PET/SPECT molecular imaging in clinical neuroscience: recent advances in the investigation of CNS diseases. Quant Imaging Med Surg 5(3): 433-47. (2015).
Zhang X, Tian Y, Zhang C, Tian X, Ross AW, Moir RD, et al. Near-infrared fluorescence molecular imaging of amyloid beta species and monitoring therapy in animal models of Alzheimer’s disease. Proc Natl Acad Sci 112(31): 9734-9. (2015).
Staderini M, Martín MA, Bolognesi ML, Menéndez JC. Imaging of β-amyloid plaques by near infrared fluorescent tracers: a new frontier for chemical neuroscience. Chem Soc Rev 44(7): 1807-19. (2015).
Kepp KP. Bioinorganic chemistry of Alzheimer’s disease. Chem Rev 112(10): 5193-239. (2012).
Govindaraju T, Rajasekhar K, Chakrabarti M. Function and toxicity of amyloid beta and recent therapeutic interventions targeting amyloid beta in Alzheimer’s disease. Chem Commun 51(70): 13434-50. (2015).
Lee SJ, Nam E, Lee HJ, Savelieff MG, Lim MH. Towards an understanding of amyloid-β oligomers: characterization, toxicity mechanisms, and inhibitors. Chem Soc Rev 46(2): 310. (2016).
Thinakaran G, Koo EH. Amyloid precursor protein trafficking, processing, and function. J Biol Chem 283(44): 29615-9. (2008).
Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 8(2): 101-12. (2007).
Caughey B, Peter T, Lansbury J. Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci 26(1): 267-98. (2003).
Walsh DM, Selkoe DJ. Abeta Oligomers - a decade of discovery. J Neurochem 101(5): 13. (2007).
Cummings JL, Morstorf T. Zhong KJAsR, Therapy. Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther 6(4): 37. (2014).
Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, et al. Two Phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s Disease. N Engl J Med 370(4): 322-33. (2014).
Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. Phase 3 Trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 370(4): 311-21. (2014).
Sciacca Michele FM, Kotler Samuel A, Brender Jeffrey R, Chen J, Lee D-K, et al. Two-Step mechanism of membrane disruption by aβ through membrane fragmentation and pore formation. Biophys J 103(4): 702-10. (2012).
Talantova M, Sanz-Blasco S, Zhang X, Xia P, Akhtar MW, Okamoto S-i, et al. Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc Nat Acad USA 110(27): E2518-7. (2013).
Um JW, Nygaard HB, Heiss JK, Kostylev MA, Stagi M, Vortmeyer A, et al. Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nat Neurosci 15: 1227. (2012).
Hsia AY, Masliah E, McConlogue L, Yu G-Q, Tatsuno G, Hu K, et al. Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models. Proc Nat Acad USA 96(6): 3228-33. (1999).
Liu H, Yang J, Wang L, Xu Y, Zhang S, Lv J, et al. Targeting β-amyloid plaques and oligomers: development of near-IR fluorescence imaging probes. Future Med Chem 9(2): 179-98. (2017).
Loudet A, Burgess K. BODIPY dyes and their derivatives: syntheses and spectroscopic properties. Chem Rev 107(11): 4891-932. (2007).
Smith NW, Alonso A, Brown CM, Dzyuba SV. Triazole-containing BODIPY dyes as novel fluorescent probes for soluble oligomers of amyloid Abeta1-42 peptide. Biochem Biophys Res Commun 391(3): 1455-8. (2010).
Teoh CL, Su D, Sahu S, Yun SW, Drummond E, Prelli F, et al. Chemical fluorescent probe for detection of Aβ oligomers. J Am Chem Soc 13(42): 13503. (2015).
Lührs T, Ritter C, Adrian M, Riek-Loher D, Bohrmann B, Döbeli H, et al. 3D structure of Alzheimer’s amyloid-β (1-42) fibrils. Proc Natl Acad Sci 102(48): 17342-7. (2005).
Ryu EK, Choe YS, Lee KH, Choi Y, Kim BT. Curcumin and dehydrozingerone derivatives: synthesis, radiolabeling, and evaluation for beta-amyloid plaque imaging. J Med Chem 49(20): 6111-9. (2006).
Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, et al. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem 280(7): 5892-901. (2005).
Ran C, Xu X, Raymond SB, Ferrara BJ, Neal K, Bacskai BJ, et al. Design, synthesis, and testing of difluoroboron-derivatized curcumins as near-infrared probes for in vivo detection of amyloid-beta deposits. J Am Chem Soc 131(42): 15257-61. (2009).
Zhang X, Tian Y, Li Z, Tian X, Sun H, Liu H, et al. Design and synthesis of curcumin analogues for in vivo fluorescence imaging and inhibiting copper-induced cross-linking of amyloid beta species in Alzheimer’s disease. J Am Chem Soc 135(44): 16397. (2013).
Zhang X, Tian Y, Zhang C, Tian X, Ross AW, Moir RD, et al. Near-infrared fluorescence molecular imaging of amyloid beta species and monitoring therapy in animal models of Alzheimer’s disease. Proc Natl Acad Sci USA 112(31): 9734. (2015).
Li Y, Yang J, Liu H, Yang J, Du L, Feng H, et al. Tuning the stereo-hindrance of a curcumin scaffold for the selective imaging of the soluble forms of amyloid beta species. Chem Sci 8(11): 7710-7. (2017).
Perchiacca JM, Ladiwala ARA, Bhattacharya M, Tessier PM. Structure-based design of conformation- and sequence-specific antibodies against amyloid β. Proc Natl Acad Sci USA 109(1): 84. (2012).
Li Y, Xu D, Ho SL, Li HW, Yang R, Wong MS. A theranostic agent for in vivo near-infrared imaging of beta-amyloid species and inhibition of beta-amyloid aggregation. Biomaterials 94: 84-92. (2016).
Li Y, Xu D, Sun A, Ho S-L, Poon C-Y, Chan H-N, et al. Fluoro-substituted cyanine for reliable in vivo labelling of amyloid-[small beta] oligomers and neuroprotection against amyloid-[small beta] induced toxicity. Chem Sci (2017).
Cao K, Farahi M, Dakanali M, Chang WM, Sigurdson CJ, Theodorakis EA, et al. Aminonaphthalene 2-cyanoacrylate (ANCA) probes fluorescently discriminate between amyloid-β and prion plaques in brain. J Am Chem Soc 134(42): 17338-41. (2012).
Lv G, Sun A, Wei P, Zhang N, Lan H, Yi T. A spiropyran-based fluorescent probe for the specific detection of beta-amyloid peptide oligomers in Alzheimer’s disease. Chem Commun 52(57): 8865-8. (2016).
Alies B, Eury H, Essassi EM, Pratviel G, Hureau C, Faller P. Concept for simultaneous and specific in situ monitoring of amyloid oligomers and fibrils via Förster resonance energy transfer. Anal Chem 86(23): 11877-82. (2014).
Mangialasche F, Solomon A, Winblad B, Mecocci P, Kivipelto M. Alzheimer’s disease: clinical trials and drug development. Lancet Neurol 9(7): 702-16. (2010).
Chimon S, Shaibat MA, Jones CR, Calero DC, Aizezi B, Ishii Y. Evidence of fibril-like beta-sheet structures in a neurotoxic amyloid intermediate of Alzheimer’s beta-amyloid. [J] Nat Struct Mol Biol 14(12): 1157-64. (2007).
Murakami K. Conformation-specific antibodies to target amyloid beta oligomers and their application to immunotherapy for Alzheimer’s disease. Biosci Biotechnol Biochem 78(8): 1293-305. (2014).
Heinz H, Stefan B, Andreas S, Boris L, Reinhold M, Volker N, et al. Generation and therapeutic efficacy of highly oligomer-specific beta-amyloid antibodies. J Neurosci 30(31): 10369. (2010).
Hillen H, Barghorn S, Labkovsky B, et al. inventors Humanized antibodies which bind to Abeta (1-42) globulomer and uses thereof WO. Patent 150946 (2008).
Kayed R, Glabe C. G et al. Inventors Methods and compositions for eliciting an amyloid-selective immune response WO. Patent 011999 (2010).
Rakez K, Elizabeth H, Thompson JL, Mcintire TM, Milton SC, Cotman CW, et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300(5618): 486-9. (2003).
Habicht G, Haupt C, Friedrich RP, Hortschansky P, Sachse C, Meinhardt J, et al. Directed selection of a conformational antibody domain that prevents mature amyloid fibril formation by stabilizing Aβ protofibrils. Proc Natl Acad Sci USA 104(49): 19232-7. (2007).
Morgado I, Wieligmann K, Bereza M, Rönicke R, Meinhardt K, Annamalai K, et al. Molecular basis of β-amyloid oligomer recognition with a conformational antibody fragment. Proc Natl Acad Sci USA 109(31): 12503. (2012).
Herzig M, Nostrand W, Jucker M. Mechanism of cerebral beta-amyloid angiopathy: murine and cellular models. Brain Pathol 16(1): 40-54. (2006).
Rakez Kayed inventor Methods and compositions related publication classification to amyloid-beta-42 oligomers US. Patent 0096476 (2017).
Brännström K, Lindhagen-Persson M, Gharibyan AL, Iakovleva I, Vestling M, Sellin ME, et al. A generic method for design of oligomer-specific antibodies. PLoS One 9(3)e90857 (2014).
Mary J. Savage, Chester Springs, Paul J, Shughrue. et al. Inventors Method for amyloid beta oligomers in a fluid sample and uses thereof ) US. Patent 0120037A1 (2014).
Perchiacca JM, Ladiwala AR, Bhattacharya M, Tessier PM. Structure-based design of conformation- and sequence-specific antibodies against amyloid beta. [J] Proc Natl Acad Sci USA 109(1): 84-9. (2012).
Ladiwala ARA, Bhattacharya M, Perchiacca JM, Cao P, Raleigh DP, Abedini A, et al. Rational design of potent domain antibody inhibitors of amyloid fibril assembly. Proc Natl Acad Sci USA 109(49): 19965-70. (2012).
Moroncini G, Kanu N, Solforosi L, Abalos G, Telling GC, Head M, et al. Motif-grafted antibodies containing the replicative interface of cellular PrP are specific for PrPSc. Proc Natl Acad Sci USA 101(28): 10404-9. (2004).
WisniewskI Thomas, M.Rakez inventors Specific murine and humanized monoclonal antibodies detecting pathology associated secondary structure changes in proteins and peptides WO. Patent 018031Al. (2018).
Mary P. Lambert, Pauline T.Velasco, Lei Chang et al. Inventors Monoclonal antibodies that target pathological assemblies of amyloid beta (abeta) US0330837A1 (2013).
Lambert MP, Velasco PT, Chang L, Viola KL, Fernandez S, Lacor PN, et al. Monoclonal antibodies that target pathological assemblies of Aβ. J Neurochem 100(1): 23-35. (2007).
Shughrue PJ, Acton PJ, Breese RS, Zhao WQ, Chen-Dodson E, Hepler RW, et al. Anti-ADDL antibodies differentially block oligomer binding to hippocampal neurons. Neurobiol Aging 31(2): 189-202. (2010).
Zhou Y, Liu L, Hao Y, Xu M. Detection of Aβ Monomers and Oligomers: Early Diagnosis of Alzheimer’s Disease. Proc Natl Acad Sci USA 11(6): 805-17. (2016).
Yang M, Yi X, Wang J, Zhou F. Electroanalytical and surface plasmon resonance sensors for detection of breast cancer and Alzheimer’s disease biomarkers in cells and body fluids. The Analyst 139(8): 1814-25. (2014).
Tsukakoshi K, Abe K, Sode K, Ikebukuro K. Selection of DNA aptamers that recognize α-synuclein oligomers using a competitive screening method. Anal Chem 84(13): 5542-7. (2012).
Zhou . Yanli,Liu Lantao,Chang zhu et al. Inventors A kind of immunoid electricity for detecting amyloid beta oligomers Chemical sensors and their preparation methods CN. Patent 1056518409 (2016).
Zhou Yanli, Li . Congming,Zhu Xu et al. Inventors Nucleic acid adaptor electrochemical sensor based on the metal organic frame material as signal probe CN. Patent 108169303 (2017).
Zhou Y, Li C, Li X, Zhu X, Ye B, Xu M. A sensitive aptasensor for the detection of β-amyloid oligomers based on metal-organic frameworks as electrochemical signal probes. Anal Methods 10(36): 4430-7. (2018).
Li H, Xie H, Cao Y, Ding X, Yin Y, Li G. A general way to assay protein by coupling peptide with signal reporter via supermolecule formation. Anal Chem 85(2): 1047-52. (2013).
Rushworth JV, Ahmed A, Griffiths HH, Pollock NM, Hooper NM, Millner PA. A label-free electrical impedimetric biosensor for the specific detection of Alzheimer’s amyloid-beta oligomers. Biosens Bioelectron 56: 83-90. (2014).
Liu L, Xia N, Jiang M, Huang N, Guo S, Li S, et al. Electrochemical detection of amyloid-β oligomer with the signal amplification of alkaline phosphatase plus electrochemical-chemical-chemical redox cycling. J Electroanal Chem 754: 40-5. (2015).
Xia N, Wang X, Zhou B, Wu Y, Mao W, Liu L. Electrochemical detection of amyloid-β oligomers based on the signal amplification of a network of silver nanoparticles. ACS Appl Mater Interfaces 8(30): 19303-11. (2016).
Qin J, Jo DG, Cho M, Lee Y. Monitoring of early diagnosis of Alzheimer’s disease using the cellular prion protein and poly (pyrrole-2-carboxylic acid) modified electrode. Biosens Bioelectron 113: 82-7. (2018).
Li H, Cao Y, Wu X, Ye Z, Li G. Peptide-based electrochemical biosensor for amyloid β 1-42 soluble oligomer assay. Talanta 93: 358-63. (2012).
Qin J, Park JS, Jo DG, Cho M, Lee Y. Curcumin-based electrochemical sensor of amyloid-β oligomer for the early detection of Alzheimer’s disease. Sens Actuators B Chem 273: 1593-9. (2018).
Kaushik A, Jayant RD, Tiwari S, Vashist A, Nair M. Nano-biosensors to detect beta-amyloid for Alzheimer's disease management Biosens Bioelectron 80: 273-87 (2 016)
Kaushik A, Shah P, Vabbina PK, Jayant RD, Tiwari S, Vashist A, et al. A label-free electrochemical immunosensor for beta-amyloid detection. Anal Methods 8(31): 6115-20. (2016).
Tucker S, Möller C, Tegerstedt K, Lord A, Laudon H, Sjödahl J, et al. The murine version of BAN2401 (mAb158) selectively reduces amyloid-β protofibrils in brain and cerebrospinal fluid of tg-ArcSwe mice. J Alzheimers Dis 43(2): 575-88. (2015).

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