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Current Alzheimer Research

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

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Research Article

Targeting Pathological Amyloid Aggregates with Conformation-Sensitive Antibodies

Author(s): Alessandra Bigi, Gilda Loffredo, Roberta Cascella* and Cristina Cecchi*

Volume 17, Issue 8, 2020

Page: [722 - 734] Pages: 13

DOI: 10.2174/1567205017666201109093848

Price: $65

Abstract

Background: The pathogenesis of Alzheimer's disease (AD) is not directly caused by the presence of senile plaques but rather by the detrimental effects exerted on neuronal cells by toxic soluble oligomers. Such species are formed early during the aggregation process of the Aβ1-42 peptide or can be released from mature fibrils. Nowadays, efficient tools for an early diagnosis, as well as pharmaceutical treatments targeting the harmful agents in samples of AD patients, are still missing.

Objective: By integrating in vitro immunochemical assay with in vivo neuronal models of toxicity, we aim to understand and target the principles that drive toxicity in AD.

Methods: We evaluated the specificity and sensitivity of A11 and OC conformational antibodies to target a range of pathologically relevant amyloid conformers and rescue their cytotoxic effects in neuronal culture models using a number of cellular readouts.

Results: We demonstrated the peculiar ability of conformational antibodies to label pathologically relevant Aβ1-42 oligomers and fibrils and to prevent their detrimental effects on neuronal cells.

Conclusion: Our results substantially improve our knowledge on the role of toxic assemblies in neurodegenerative diseases, thus suggesting new and more effective diagnostic and therapeutic tools for AD.

Keywords: Conformation-sensitive antibodies, amyloid-β peptide, toxic oligomers, amyloid fibrils, Alzheimer's disease, protein aggregation.

« Previous Next »
[1]
Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 2016; 8(6): 595-608.
[http://dx.doi.org/10.15252/emmm.201606210] [PMID: 27025652]
[2]
De Strooper B, Karran E. The cellular phase of Alzheimer’s disease. Cell 2016; 164(4): 603-15.
[http://dx.doi.org/10.1016/j.cell.2015.12.056] [PMID: 26871627]
[3]
Scheltens P, Blennow K, Breteler MMB, et al. Alzheimer’s disease. Lancet 2016; 388(10043): 505-17.
[http://dx.doi.org/10.1016/S0140-6736(15)01124-1] [PMID: 26921134]
[4]
Chiti F, Dobson CM. Protein misfolding, amyloid formation, and human disease: A summary of progress over the last decade. Annu Rev Biochem 2017; 86: 27-68.
[http://dx.doi.org/10.1146/annurev-biochem-061516-045115] [PMID: 28498720]
[5]
Chow VW, Mattson MP, Wong PC, Gleichmann M. An overview of APP processing enzymes and products. Neuromolecular Med 2010; 12(1): 1-12.
[http://dx.doi.org/10.1007/s12017-009-8104-z] [PMID: 20232515]
[6]
Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: Lessons from the Alzheimer’s amyloid β-peptide. Nat Rev Mol Cell Biol 2007; 8(2): 101-12.
[http://dx.doi.org/10.1038/nrm2101] [PMID: 17245412]
[7]
Agrawal N, Skelton AA. Structure and function of Alzheimer’s amyloid β proteins from monomer to fibrils: A mini review. Protein J 2019; 38(4): 425-34.
[http://dx.doi.org/10.1007/s10930-019-09854-3] [PMID: 31325011]
[8]
Sakono M, Zako T. Amyloid oligomers: Formation and toxicity of Abeta oligomers. FEBS J 2010; 277(6): 1348-58.
[http://dx.doi.org/10.1111/j.1742-4658.2010.07568.x] [PMID: 20148964]
[9]
Ferreira ST, Klein WL. The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease. Neurobiol Learn Mem 2011; 96(4): 529-43.
[http://dx.doi.org/10.1016/j.nlm.2011.08.003] [PMID: 21914486]
[10]
Benilova I, Karran E, De Strooper B. The toxic Aβ oligomer and Alzheimer’s disease: An emperor in need of clothes. Nat Neurosci 2012; 15(3): 349-57.
[http://dx.doi.org/10.1038/nn.3028] [PMID: 22286176]
[11]
Sengupta U, Nilson AN, Kayed R. The Role of Amyloid-β Oligomers in toxicity, propagation, and immunotherapy. EBioMedicine 2016; 6: 42-9.
[http://dx.doi.org/10.1016/j.ebiom.2016.03.035] [PMID: 27211547]
[12]
Kayed R, Lasagna-Reeves CA. Molecular mechanisms of amyloid oligomers toxicity. J Alzheimers Dis 2013; 33(1): S67-78.
[http://dx.doi.org/10.3233/JAD-2012-129001] [PMID: 22531422]
[13]
Evangelisti E, Zampagni M, Cascella R, et al. Plasma membrane injury depends on bilayer lipid composition in Alzheimer’s disease. J Alzheimers Dis 2014; 41(1): 289-300.
[http://dx.doi.org/10.3233/JAD-131406] [PMID: 24614900]
[14]
Cheignon C, Tomas M, Bonnefont-Rousselot D, Faller P, Hureau C, Collin F. Oxidative stress and the amyloid beta peptide in Alzheimer’s disease. Redox Biol 2018; 14: 450-64.
[http://dx.doi.org/10.1016/j.redox.2017.10.014] [PMID: 29080524]
[15]
Jackson MP, Hewitt EW. Cellular proteostasis: Degradation of misfolded proteins by lysosomes. Essays Biochem 2016; 60(2): 173-80.
[http://dx.doi.org/10.1042/EBC20160005] [PMID: 27744333]
[16]
Minter MR, Taylor JM, Crack PJ. The contribution of neuroinflammation to amyloid toxicity in Alzheimer’s disease. J Neurochem 2016; 136(3): 457-74.
[http://dx.doi.org/10.1111/jnc.13411] [PMID: 26509334]
[17]
Cascella R, Evangelisti E, Bigi A, et al. Soluble oligomers require a ganglioside to trigger neuronal calcium overload. J Alzheimers Dis 2017; 60(3): 923-38.
[http://dx.doi.org/10.3233/JAD-170340] [PMID: 28922156]
[18]
Glabe CG. Structural classification of toxic amyloid oligomers. J Biol Chem 2008; 283(44): 29639-43.
[http://dx.doi.org/10.1074/jbc.R800016200] [PMID: 18723507]
[19]
De Genst E, Messer A, Dobson CM. Antibodies and protein misfolding: From structural research tools to therapeutic strategies. Biochim Biophys Acta 2014; 1844(11): 1907-19.
[http://dx.doi.org/10.1016/j.bbapap.2014.08.016] [PMID: 25194824]
[20]
Lambert MP, Barlow AK, Chromy BA, et al. Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA 1998; 95(11): 6448-53.
[http://dx.doi.org/10.1073/pnas.95.11.6448] [PMID: 9600986]
[21]
Lambert MP, Viola KL, Chromy BA, et al. Vaccination with soluble Abeta oligomers generates toxicity-neutralizing antibodies. J Neurochem 2001; 79(3): 595-605.
[http://dx.doi.org/10.1046/j.1471-4159.2001.00592.x] [PMID: 11701763]
[22]
Ladiwala ARA, Litt J, Kane RS, et al. Conformational differences between two amyloid β oligomers of similar size and dissimilar toxicity. J Biol Chem 2012; 287(29): 24765-73.
[http://dx.doi.org/10.1074/jbc.M111.329763] [PMID: 22547072]
[23]
Kayed R, Head E, Thompson JL, et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 2003; 300(5618): 486-9.
[http://dx.doi.org/10.1126/science.1079469] [PMID: 12702875]
[24]
Kayed R, Head E, Sarsoza F, et al. Fibril specific, conformation dependent antibodies recognize a generic epitope common to amyloid fibrils and fibrillar oligomers that is absent in prefibrillar oligomers. Mol Neurodegener 2007; 2: 18.
[http://dx.doi.org/10.1186/1750-1326-2-18] [PMID: 17897471]
[25]
Kim KS, Miller DL, Sapienza VJ, et al. Production and characterization of monoclonal antibodies reactive to synthetic cerebrovascular amyloid peptide. Neurosci Res Commun 1988; 2: 121-30.
[26]
Kim KS, Wen GY, Bancher C, et al. Detection and quantita-tion of amyloid beta-peptide with 2 monoclonal antibodies. Neurosci Res Commun 1990; 113-22.
[27]
Vivoli Vega M, Cascella R, Chen SW, et al. The toxicity of misfolded protein oligomers is independent of their secondary structure. ACS Chem Biol 2019; 14(7): 1593-600.
[http://dx.doi.org/10.1021/acschembio.9b00324] [PMID: 31074957]
[28]
Mosmann T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J Immunol Methods 1983; 65(1-2): 55-63.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]
[29]
Ramshini H, Tayebee R, Bigi A, Bemporad F, Cecchi C, Chiti F. Identification of novel 1,3,5-triphenylbenzene derivative compounds as inhibitors of hen lysozyme amyloid fibril formation. Int J Mol Sci 2019; 20(22): 5558.
[http://dx.doi.org/10.3390/ijms20225558] [PMID: 31703381]
[30]
Thornberry NA, Rano TA, Peterson EP, et al. A combinatorial approach defines specificities of members of the caspase family and granzyme B. Functional relationships established for key mediators of apoptosis. J Biol Chem 1997; 272(29): 17907-11.
[http://dx.doi.org/10.1074/jbc.272.29.17907] [PMID: 9218414]
[31]
Evangelisti E, Cascella R, Becatti M, et al. Binding affinity of amyloid oligomers to cellular membranes is a generic indicator of cellular dysfunction in protein misfolding diseases. Sci Rep 2016; 6: 32721.
[http://dx.doi.org/10.1038/srep32721] [PMID: 27619987]
[32]
Marx J. Alzheimer’s disease. Fresh evidence points to an old suspect: Calcium. Science 2007; 318(5849): 384-5.
[http://dx.doi.org/10.1126/science.318.5849.384] [PMID: 17947560]
[33]
Demuro A, Parker I, Stutzmann GE. Calcium signaling and amyloid toxicity in Alzheimer disease. J Biol Chem 2010; 285(17): 12463-8.
[http://dx.doi.org/10.1074/jbc.R109.080895] [PMID: 20212036]
[34]
Evangelisti E, Wright D, Zampagni M, et al. Lipid rafts mediate amyloid-induced calcium dyshomeostasis and oxidative stress in Alzheimer’s disease. Curr Alzheimer Res 2013; 10(2): 143-53.
[http://dx.doi.org/10.2174/1567205011310020004] [PMID: 22950913]
[35]
Wang Y, Shi Y, Wei H. Calcium dysregulation in Alzheimer’s disease: A target for new drug development. J Alzheimers Dis Parkinsonism 2017; 7(5): 374.
[http://dx.doi.org/10.4172/2161-0460.1000374] [PMID: 29214114]
[36]
Banchelli M, Cascella R, D’Andrea C, Cabaj L, Osticioli I, Ciofini D, et al. Nanoscopic insights into the surface conformation of neurotoxic amyloid β oligomers. RSC Advances 2020; 10: 21907.
[http://dx.doi.org/10.1039/D0RA03799K]
[37]
Oddo S, Caccamo A, Shepherd JD, et al. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: Intracellular Abeta and synaptic dysfunction. Neuron 2003; 39(3): 409-21.
[http://dx.doi.org/10.1016/S0896-6273(03)00434-3] [PMID: 12895417]
[38]
Chen GF, Xu TH, Yan Y, et al. Amyloid beta: Structure, biology and structure-based therapeutic development. Acta Pharmacol Sin 2017; 38(9): 1205-35.
[http://dx.doi.org/10.1038/aps.2017.28] [PMID: 28713158]
[39]
Barton J, Arias DS, Niyangoda C, et al. Kinetic transition in amyloid assembly as a screening assay for oligomer-selective dyes. Biomolecules 2019; 9(10): 539.
[http://dx.doi.org/10.3390/biom9100539] [PMID: 31569739]
[40]
O’Nuallain B, Wetzel R. Conformational Abs recognizing a generic amyloid fibril epitope. Proc Natl Acad Sci USA 2002; 99(3): 1485-90.
[http://dx.doi.org/10.1073/pnas.022662599] [PMID: 11818542]
[41]
Lambert MP, Velasco PT, Viola KL, Klein WL. Targeting generation of antibodies specific to conformational epitopes of amyloid beta-derived neurotoxins. CNS Neurol Disord Drug Targets 2009; 8(1): 65-81.
[http://dx.doi.org/10.2174/187152709787601876] [PMID: 19275637]
[42]
Haupt C, Morgado I, Kumar ST, et al. Amyloid fibril recognition with the conformational B10 antibody fragment depends on electrostatic interactions. J Mol Biol 2011; 405(2): 341-8.
[http://dx.doi.org/10.1016/j.jmb.2010.10.059] [PMID: 21059358]
[43]
Morgado I, Wieligmann K, Bereza M, et al. Molecular basis of β-amyloid oligomer recognition with a conformational antibody fragment. Proc Natl Acad Sci USA 2012; 109(31): 12503-8.
[http://dx.doi.org/10.1073/pnas.1206433109] [PMID: 22814377]
[44]
Farlow MR, Brosch JR. Immunotherapy for Alzheimer’s disease. Neurol Clin 2013; 31(3): 869-78.
[http://dx.doi.org/10.1016/j.ncl.2013.03.012] [PMID: 23896510]
[45]
Goure WF, Krafft GA, Jerecic J, Hefti F. Targeting the proper amyloid-beta neuronal toxins: a path forward for Alzheimer’s disease immunotherapeutics. Alzheimers Res Ther 2014; 6(4): 42.
[http://dx.doi.org/10.1186/alzrt272] [PMID: 25045405]
[46]
Sebollela A, Cline EN, Popova I, et al. A human scFv antibody that targets and neutralizes high molecular weight pathogenic amyloid-β oligomers. J Neurochem 2017; 142(6): 934-47.
[http://dx.doi.org/10.1111/jnc.14118] [PMID: 28670737]
[47]
Calamai M, Evangelisti E, Cascella R, et al. Single molecule experiments emphasize GM1 as a key player of the different cytotoxicity of structurally distinct Aβ1-42 oligomers. Biochim Biophys Acta 2016; 1858(2): 386-92.
[http://dx.doi.org/10.1016/j.bbamem.2015.12.009] [PMID: 26656159]
[48]
Wu J, Lambert MP, Velasco P, et al. Oligomeric and fibrillar amyloid-beta42 studied by Cryo-TEM. Microsc Microanal 2009; 15: 944-5.
[http://dx.doi.org/10.1017/S1431927609095762]
[49]
Gong Y, Chang L, Viola KL, et al. Alzheimer’s disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc Natl Acad Sci USA 2003; 100(18): 10417-22.
[http://dx.doi.org/10.1073/pnas.1834302100] [PMID: 12925731]
[50]
Dahlgren KN, Manelli AM, Stine WB Jr, Baker LK, Krafft GA, LaDu MJ. Oligomeric and fibrillar species of amyloid-beta peptides differentially affect neuronal viability. J Biol Chem 2002; 277(35): 32046-53.
[http://dx.doi.org/10.1074/jbc.M201750200] [PMID: 12058030]
[51]
Kayed R, Sokolov Y, Edmonds B, et al. Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases. J Biol Chem 2004; 279(45): 46363-6.
[http://dx.doi.org/10.1074/jbc.C400260200] [PMID: 15385542]
[52]
Quist A, Doudevski I, Lin H, et al. Amyloid ion channels: A common structural link for protein-misfolding disease. Proc Natl Acad Sci USA 2005; 102(30): 10427-32.
[http://dx.doi.org/10.1073/pnas.0502066102] [PMID: 16020533]
[53]
Sciacca MF, Kotler SA, Brender JR, Chen J, Lee DK, Ramamoorthy A. Two-step mechanism of membrane disruption by Aβ through membrane fragmentation and pore formation. Biophys J 2012; 103(4): 702-10.
[http://dx.doi.org/10.1016/j.bpj.2012.06.045] [PMID: 22947931]
[54]
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 2017; 46(2): 310-23.
[http://dx.doi.org/10.1039/C6CS00731G] [PMID: 27878186]
[55]
Gibbs E, Silverman JM, Zhao B, et al. A rationally designed humanized antibody selective for amyloid beta oligomers in Alzheimer’s disease. Sci Rep 2019; 9(1): 9870.
[http://dx.doi.org/10.1038/s41598-019-46306-5] [PMID: 31285517]
[56]
Zhang Y, Huai Y, Zhang X, Song C, Cai J, Zhang Y. The mode of action of an anti-oligomeric amyloid β-protein antibody affects its protective efficacy. Neurotox Res 2019; 35(2): 304-17.
[http://dx.doi.org/10.1007/s12640-018-9955-6] [PMID: 30229545]
[57]
Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM. Intraneuronal Abeta causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron 2005; 45(5): 675-88.
[http://dx.doi.org/10.1016/j.neuron.2005.01.040] [PMID: 15748844]
[58]
Xiao C, Davis FJ, Chauhan BC, et al. Brain transit and ameliorative effects of intranasally delivered anti-amyloid-β oligomer antibody in 5XFAD mice. J Alzheimers Dis 2013; 35(4): 777-88.
[http://dx.doi.org/10.3233/JAD-122419] [PMID: 23542865]
[59]
Wang HC, Yu YZ, Liu S, Zhao M, Xu Q. Peripherally administered sera antibodies recognizing amyloid-β oligomers mitigate Alzheimer’s disease-like pathology and cognitive decline in aged 3× Tg-AD mice. Vaccine 2016; 34(15): 1758-66.
[http://dx.doi.org/10.1016/j.vaccine.2016.02.056] [PMID: 26945100]
[60]
Marciani DJ. Rejecting the Alzheimer’s disease vaccine development for the wrong reasons. Drug Discov Today 2017; 22(4): 609-14.
[http://dx.doi.org/10.1016/j.drudis.2016.10.012] [PMID: 27989721]
[61]
Marciani DJ. Promising results from Alzheimer’s disease passive immunotherapy support the development of a preventive vaccine. Research (Wash D C) 2019; 20195341375
[http://dx.doi.org/10.34133/2019/5341375] [PMID: 31549066]
[62]
Liu YH, Bu XL, Liang CR, et al. An N-terminal antibody promotes the transformation of amyloid fibrils into oligomers and enhances the neurotoxicity of amyloid-beta: The dust-raising effect. J Neuroinflammation 2015; 12: 153.
[http://dx.doi.org/10.1186/s12974-015-0379-4] [PMID: 26311039]
[63]
Busche MA, Grienberger C, Keskin AD, et al. Decreased amyloid-β and increased neuronal hyperactivity by immunotherapy in Alzheimer’s models. Nat Neurosci 2015; 18(12): 1725-7.
[http://dx.doi.org/10.1038/nn.4163] [PMID: 26551546]
[64]
Lee JC, Kim SJ, Hong S, Kim Y. Diagnosis of Alzheimer’s disease utilizing amyloid and tau as fluid biomarkers. Exp Mol Med 2019; 51(5): 1-10.
[http://dx.doi.org/10.1038/s12276-019-0250-2] [PMID: 31073121]
[65]
Meng X, Li T, Wang X, et al. Association between increased levels of amyloid-β oligomers in plasma and episodic memory loss in Alzheimer’s disease. Alzheimers Res Ther 2019; 11(1): 89.
[http://dx.doi.org/10.1186/s13195-019-0535-7] [PMID: 31651358]
[66]
Shughrue PJ, Acton PJ, Breese RS, et al. Anti-ADDL antibodies differentially block oligomer binding to hippocampal neurons. Neurobiol Aging 2010; 31(2): 189-202.
[http://dx.doi.org/10.1016/j.neurobiolaging.2008.04.003] [PMID: 18486276]
[67]
Hillen H, Barghorn S, Striebinger A, et al. Generation and therapeutic efficacy of highly oligomer-specific beta-amyloid antibodies. J Neurosci 2010; 30(31): 10369-79.
[http://dx.doi.org/10.1523/JNEUROSCI.5721-09.2010] [PMID: 20685980]

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