Challenges in understanding the structure/activity relationship of Aβ oligomers

Albert W. Pilkington IV; Justin Legleiter; Albert W. Pilkington IV; Justin Legleiter

doi:10.3934/biophy.2019.1.1

AIMS Biophysics

2019, Volume 6, Issue 1: 1-22. doi: 10.3934/biophy.2019.1.1

Previous Article Next Article

Review Special Issues

Challenges in understanding the structure/activity relationship of Aβ oligomers

Albert W. Pilkington IV ¹,
Justin Legleiter ^{1,2,3
,
,}

1.
The C. Eugene Bennett Department of Chemistry, West Virginia University, 217 Clark Hall, P.O. Box 6045, Morgantown, West Virginia 26505, United States
2.
Blanchette Rockefeller Neurosciences Institutes, West Virginia University, 1 Medical Center Dr., P.O. Box 9303, Morgantown, West Virginia 26505, United States
3.
Department of Neuroscience, West Virginia University, 1 Medical Center Dr., P.O. Box 9303, Morgantown, West Virginia 26505, United States

Received: 05 November 2018 Accepted: 07 January 2019 Published: 10 January 2019

A major hallmark of Alzheimer’s disease (AD) is the accumulation and deposition of fibrillar aggregates of the amyloid-b (Ab) peptide into neuritic plaques. These amyloid deposits were thought to play a central role in AD; however, the correlation between plaque load and disease is weak. Increasing evidence supports the notion that a variety of small, globular aggregates of Ab, referred to broadly as Ab oligomers (AbO), may in fact be the primary culprits associated with neurotoxicity. Evaluation of AbO structure and physiological activity is complicated by their metastability, heterogeneity, complex aggregation pathways, and dependence on experimental conditions. Numerous different types of oligomers have been reported, and these have been associated with varying degrees of toxicity and modes of interaction. Here, we briefly review AbOs with a focus on their formation, structure, and biophysical methods applied to their investigation.
- Alzheimer’s disease,
- β-amyloid,
- oligomers,
- neurodegeneration,
- protein aggregation
Citation: Albert W. Pilkington IV, Justin Legleiter. Challenges in understanding the structure/activity relationship of Aβ oligomers[J]. AIMS Biophysics, 2019, 6(1): 1-22. doi: 10.3934/biophy.2019.1.1

Related Papers:

Abstract

A major hallmark of Alzheimer’s disease (AD) is the accumulation and deposition of fibrillar aggregates of the amyloid-b (Ab) peptide into neuritic plaques. These amyloid deposits were thought to play a central role in AD; however, the correlation between plaque load and disease is weak. Increasing evidence supports the notion that a variety of small, globular aggregates of Ab, referred to broadly as Ab oligomers (AbO), may in fact be the primary culprits associated with neurotoxicity. Evaluation of AbO structure and physiological activity is complicated by their metastability, heterogeneity, complex aggregation pathways, and dependence on experimental conditions. Numerous different types of oligomers have been reported, and these have been associated with varying degrees of toxicity and modes of interaction. Here, we briefly review AbOs with a focus on their formation, structure, and biophysical methods applied to their investigation.

Acknowledgments

Previous support from the National Science Foundation (NSF#1054211), and the Alzheimer's Association (NIRG-11-203834) is gratefully appreciated.

Conflict of interest

The authors declare no conflicts of interest.

References

[1]	Knowles TP, Vendruscolo M, Dobson CM (2014) The amyloid state and its association with protein misfolding diseases. Nat Rev Mol Cell Biol 15: 384–396. doi: 10.1038/nrm3810
[2]	Hardy JA, Higgins GA (1992) Alzheimers disease-the amyloid cascade hyopothesis. Science 256: 184–185. doi: 10.1126/science.1566067
[3]	Arriagada PV, Growdon JH, Hedleywhyte ET, et al. (1992) Neurofibrillary tangles but not senile plaques parellel duration and severity of Alzheimers disease. Neurology 42: 631–639. doi: 10.1212/WNL.42.3.631
[4]	Terry RD, Masliah E, Salmon DP, et al. (1991) Physical basis of cognitve alterations in Alzheimers disease-synapse loss is the major correlate of cognitive impairment. Ann Neurol 30: 572–580. doi: 10.1002/ana.410300410
[5]	Viola KL, Sbarboro J, Sureka R, et al. (2015) Towards non-invasive diagnostic imaging of early-stage Alzheimer's disease. Nat Nanotechnol 10: 91–98. doi: 10.1038/nnano.2014.254
[6]	Hyman B, Tanzi R (1992) Amyloid, dementia and Alzheimer's disease. Curr Opin Neurol Neurosur 5: 88–93.
[7]	Cummings BJ, Pike CJ, Shankle R, et al. (1996) b-Amyloid deposition and other measures of neuropathology predict cognitive status in Alzheimer's disease. Neurobiol Aging 17: 921–933. doi: 10.1016/S0197-4580(96)00170-4
[8]	Cummings JL, Morstorf T, Zhong K (2014) Alzheimer's disease drug-development pipeline: Few candidates, frequent failures. Alzheimers Res Ther 6: 37. doi: 10.1186/alzrt269
[9]	Goure WF, Krafft GA, Jerecic J, et al. (2014) Targeting the proper amyloid-β neuronal toxins: A path forward for Alzheimer's disease immunotherapeutics. Alzheimers Res Ther 6: 42. doi: 10.1186/alzrt272
[10]	Karran E, Hardy J (2014) A critique of the drug discovery and phase 3 clinical programs targeting the amyloid hypothesis for Alzheimer disease. Ann Neurol 76: 185–205. doi: 10.1002/ana.24188
[11]	Karran E, Hardy J (2014) Antiamyloid therapy for Alzheimer's disease-are we on the right road? New Engl J Med 370: 377–378. doi: 10.1056/NEJMe1313943
[12]	Frackowiak J, Zoltowska A, Wisniewski HM (1994) Nonfibrillar β-amyloid protein is associated with smooth-muscle cells of vessel walls in Alzheimer disease. J Neuropath Exp Neur 53: 637–645. doi: 10.1097/00005072-199411000-00011
[13]	Oda T, Pasinetti GM, Osterburg HH, et al. (1994) Purification and characterization of brain clusterin. Biochem Bioph Res Co 204: 1131–1136. doi: 10.1006/bbrc.1994.2580
[14]	Oda T, Wals P, Osterburg HH, et al. (1995) Clusterin (apoJ) alters the aggregation of amyloid β peptide (Aβ(1-42)) and forms slowly sedimenting Aβ complexes that cuase oxidative stress. Exp Neurol 136: 22–31. doi: 10.1006/exnr.1995.1080
[15]	Esparza TJ, Zhao H, Cirrito JR, et al. (2013) Amyloid-β oligomerization in Alzheimer dementia versus high-pathology controls. Ann Neurol 73: 104–119. doi: 10.1002/ana.23748
[16]	Gong YS, Chang L, Viola KL, et al. (2003) Alzheimer's disease-affected brain: Presence of oligomeric A β ligands (ADDLs) suggests a molecular basis for reversible memory loss. P Natl Acad Sci USA 100: 10417–10422. doi: 10.1073/pnas.1834302100
[17]	Kayed R, Head E, Thompson JL, et al. (2003) Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300: 486–489. doi: 10.1126/science.1079469
[18]	Noguchi A, Matsumura S, Dezawa M, et al. (2009) Isolation and characterization of patient-derived, toxic, high mass amyloid β-protein (Aβ) assembly from Alzheimer disease brains. J Biol Chem 284: 32895–32905. doi: 10.1074/jbc.M109.000208
[19]	Pham E, Crews L, Ubhi K, et al. (2010) Progressive accumulation of amyloid-β oligomers in Alzheimer's disease and in amyloid precursor protein transgenic mice is accompanied by selective alterations in synaptic scaffold proteins. FEBS J 277: 3051–3067. doi: 10.1111/j.1742-4658.2010.07719.x
[20]	Gyure KA, Durham R, Stewart WF, et al. (2001) Intraneuronal Aβ-amyloid precedes development of amyloid plaques in Down syndrome. Arch Pathol Lab Med 125: 489–492.
[21]	Lacor PN, Buniel MC, Chang L, et al. (2004) Synaptic targeting by Alzheimer's-related amyloid β oligomers. J Neurosci 24: 10191–10200. doi: 10.1523/JNEUROSCI.3432-04.2004
[22]	Lesne SE, Sherman MA, Grant M, et al. (2013) Brain amyloid-β oligomers in ageing and Alzheimer's disease. Brain 136: 1383–1398. doi: 10.1093/brain/awt062
[23]	Georganopoulou DG, Chang L, Nam JM, et al. (2005) Nanoparticle-based detection in cerebral spinal fluid of a soluble pathogenic biomarker for Alzheimer's disease. P Natl Acad Sci USA 102: 2273–2276. doi: 10.1073/pnas.0409336102
[24]	Bruggink KA, Jongbloed W, Biemans EALM, et al. (2013) Amyloid-β oligomer detection by ELISA in cerebrospinal fluid and brain tissue. Anal Biochem 433: 112–120. doi: 10.1016/j.ab.2012.09.014
[25]	Englund H, Gunnarsson MD, Brundin RM, et al. (2009) Oligomerization partially explains the lowering of Aβ42 in Alzheimer's disease cerebrospinal fluid. Neurodegener Dis 6: 139–147. doi: 10.1159/000225376
[26]	Fukumoto H, Tokuda T, Kasai T, et al. (2010) High-molecular-weight β-amyloid oligomers are elevated in cerebrospinal fluid of Alzheimer patients. FASEB J 24: 2716–2726. doi: 10.1096/fj.09-150359
[27]	Gao CM, Yam AY, Wang X, et al. (2010) Aβ40 Oligomers identified as a potential biomarker for the diagnosis of Alzheimer's disease. PLoS One 5: e15725. doi: 10.1371/journal.pone.0015725
[28]	Herskovits AZ, Locascio JJ, Peskind ER, et al. (2013) A luminex assay detects amyloid-β oligomers in Alzheimer's disease cerebrospinal fluid. PLoS One 8: e67898. doi: 10.1371/journal.pone.0067898
[29]	Holtta M, Hansson O, Andreasson U, et al. (2013) Evaluating amyloid-β oligomers in cerebrospinal fluid as a biomarker for Alzheimer's disease. PLoS One 8: e66381. doi: 10.1371/journal.pone.0066381
[30]	Jongbloed W, Bruggink KA, Kester MI, et al. (2015) Amyloid-β oligomers relate to cognitive decline in Alzheimer's disease. J Alzheimers Dis 45: 35–43. doi: 10.3233/JAD-142136
[31]	Santos AN, Ewers M, Minthon L, et al. (2012) Amyloid-β oligomers in cerebrospinal fluid are associated with cognitive decline in patients with Alzheimer's disease. J Alzheimers Dis 29: 171–176. doi: 10.3233/JAD-2012-111361
[32]	Lesne S, Koh MT, Kotilinek L, et al. (2006) A specific amyloid-β protein assembly in the brain impairs memory. Nature 440: 352–357. doi: 10.1038/nature04533
[33]	Ono K, Condron MM, Teplow DB (2009) Structure-neurotoxicity relationships of amyloid β-protein oligomers. P Natl Acad Sci USA 106: 14745–14750. doi: 10.1073/pnas.0905127106
[34]	Quist A, Doudevski L, Lin H, et al. (2005) Amyloid ion channels: A common structural link for protein-misfolding disease. P Natl Acad Sci USA 102: 10427–10432. doi: 10.1073/pnas.0502066102
[35]	Shankar GM, Bloodgood BL, Townsend M, et al. (2007) Natural oligomers of the Alzheimer amyloid-β protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci 27: 2866–2875. doi: 10.1523/JNEUROSCI.4970-06.2007
[36]	Shankar GM, Li S, Mehta TH, et al. (2008) Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med 14: 837–842. doi: 10.1038/nm1782
[37]	Townsend M, Shankar GM, Mehta T, et al. (2006) Effects of secreted oligomers of amyloid β-protein on hippocampal synaptic plasticity: A potent role for trimers. J Physiol 572: 477–492. doi: 10.1113/jphysiol.2005.103754
[38]	Lambert MP, Barlow AK, Chromy BA, et al. (1998) Diffusible, nonfibrillar ligands derived from Aβ1-42 are potent central nervous system neurotoxins. P Natl Acad Sci USA 95: 6448–6453. doi: 10.1073/pnas.95.11.6448
[39]	Walsh DM, Klyubin I, Fadeeva JV, et al. (2002) Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416: 535–539. doi: 10.1038/416535a
[40]	Zhao J, Li A, Rajsombath M, et al. (2018) Soluble Aβ Oligomers Impair Dipolar Heterodendritic Plasticity by Activation of mGluR in the Hippocampal CA1 Region. iScience 6: 138–150. doi: 10.1016/j.isci.2018.07.018
[41]	De Felice FG, Wu D, Lambert MP, et al. (2008) Alzheimer's disease-type neuronal tau hyperphosphorylation induced by Aβ oligomers. Neurobiol Aging 29: 1334–1347. doi: 10.1016/j.neurobiolaging.2007.02.029
[42]	Ma QL, Yang F, Rosario ER, et al. (2009) β-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: Suppression by omega-3 fatty acids and curcumin. J Neurosci 29: 9078–9089. doi: 10.1523/JNEUROSCI.1071-09.2009
[43]	Resende R, Ferreiro E, Pereira C, et al. (2008) ER stress is involved in Aβ-induced GSK-3β activation and tau phosphorylation. J Neurosci Res 86: 2091–2099. doi: 10.1002/jnr.21648
[44]	Tomiyama T, Matsuyama S, Iso H, et al. (2010) A mouse model of amyloid-β oligomers: their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo. J Neurosci 30: 4845–4856. doi: 10.1523/JNEUROSCI.5825-09.2010
[45]	Zempel H, Thies E, Mandelkow E, et al. (2010) A Oligomers Cause Localized Ca²⁺ Elevation, Missorting of Endogenous Tau into Dendrites, Tau Phosphorylation, and Destruction of Microtubules and Spines. J Neurosci 30: 11938–11950. doi: 10.1523/JNEUROSCI.2357-10.2010
[46]	Heinitz K, Beck M, Schliebs R, et al. (2006) Toxicity mediated by soluble oligomers of β-amyloid(1‑42) on cholinergic SN56.B5.G4 cells. J Neurochem 98: 1930–1945. doi: 10.1111/j.1471-4159.2006.04015.x
[47]	Nunes-Tavares N, Santos LE, Stutz B, et al. (2012) Inhibition of choline acetyltransferase as a mechanism for cholinergic dysfunction induced by amyloid-β peptide oligomers. J Biol Chem 287: 19377–19385. doi: 10.1074/jbc.M111.321448
[48]	De Felice FG, Velasco PT, Lambert MP, et al. (2007) Aβ oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J Biol Chem 282: 11590–11601. doi: 10.1074/jbc.M607483200
[49]	Longo VD, Viola KL, Klein WL, et al. (2000) Reversible inactivation of superoxide-sensitive aconitase in Aβ1-42-treated neuronal cell lines. J Neurochem 75: 1977–1985.
[50]	Sponne I, Fifre A, Drouet B, et al. (2003) Apoptotic neuronal cell death induced by the non-fibrillar amyloid-β peptide proceeds through an early reactive oxygen species-dependent cytoskeleton perturbation. J Biol Chem 278: 3437–3445. doi: 10.1074/jbc.M206745200
[51]	Tabner BJ, El-Agnaf OMA, Turnbull S, et al. (2005) Hydrogen peroxide is generated during the very early stages of aggregation of the amyloid peptides implicated in Alzheimer disease and familial British dementia. J Biol Chem 280: 35789–35792. doi: 10.1074/jbc.C500238200
[52]	Alberdi E, Wyssenbach A, Alberdi M, et al. (2013) Ca²⁺-dependent endoplasmic reticulum stress correlates with astrogliosis in oligomeric amyloid β-treated astrocytes and in a model of Alzheimer's disease. Aging Cell 12: 292–302. doi: 10.1111/acel.12054
[53]	Nishitsuji K, Tomiyama T, Ishibashi K, et al. (2009) The E693Δ mutation in amyloid precursor protein increases intracellular accumulation of amyloid β oligomers and causes endoplasmic reticulum stress-induced apoptosis in cultured cells. Am J Pathol 174: 957–969. doi: 10.2353/ajpath.2009.080480
[54]	Lacor PN, Buniel MC, Furlow PW, et al. (2007) Aβ oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. J Neurosci 27: 796–807. doi: 10.1523/JNEUROSCI.3501-06.2007
[55]	Roselli F (2005) Soluble β-Amyloid_1-40 induces NMDA-dependent degradation of postsynaptic density-95 at glutamatergic synapses. J Neurosci 25: 11061–11070. doi: 10.1523/JNEUROSCI.3034-05.2005
[56]	Snyder EM, Nong Y, Almeida CG, et al. (2005) Regulation of NMDA receptor trafficking by amyloid-β. Nat Neurosci 8: 1051–1058. doi: 10.1038/nn1503
[57]	Zhao WQ, De Felice FG, Fernandez S, et al. (2007) Amyloid β oligomers induce impairment of neuronal insulin receptors. FASEB J 22: 246–260.
[58]	De Felice FG, Vieira MN, Bomfim TR, et al. (2009) Protection of synapses against Alzheimer's-linked toxins: insulin signaling prevents the pathogenic binding of Aβ oligomers. Proc Natl Acad Sci USA 106: 1971–1976. doi: 10.1073/pnas.0809158106
[59]	Koffie RM, Meyer-Luehmann M, Hashimoto T, et al. (2009) Oligomeric amyloid-β associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. P Natl Acad Sci USA 106: 4012–4017. doi: 10.1073/pnas.0811698106
[60]	Decker H, Lo KY, Unger SM, et al. (2010) Amyloid-Peptide oligomers disrupt axonal transport through an NMDA receptor-dependent mechanism that is mediated by glycogen synthase kinase 3 in primary cultured hippocampal neurons. J Neurosci 30: 9166–9171. doi: 10.1523/JNEUROSCI.1074-10.2010
[61]	Pigino G, Morfini G, Atagi Y, et al. (2009) Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid β. P Natl Acad Sci USA 106: 5907–5912. doi: 10.1073/pnas.0901229106
[62]	Poon WW, Blurton-Jones M, Tu CH, et al. (2011) β-Amyloid impairs axonal BDNF retrograde trafficking. Neurobiol Aging 32: 821–833. doi: 10.1016/j.neurobiolaging.2009.05.012
[63]	Hu J, Akama KT, Krafft GA, et al. (1998) Amyloid-β peptide activates cultured astrocytes: Morphological alterations, cytokine induction and nitric oxide release. Brain Res 785: 195–206. doi: 10.1016/S0006-8993(97)01318-8
[64]	Jimenez S, Baglietto-Vargas D, Caballero C, et al. (2008) Inflammatory response in the hippocampus of PS1M146L/APP751SL mouse model of Alzheimer's disease: Age-dependent switch in the microglial phenotype from alternative to classic. J Neurosci 28: 11650–11661. doi: 10.1523/JNEUROSCI.3024-08.2008
[65]	Bhaskar K, Miller M, Chludzinski A, et al. (2009) The PI3K-Akt-mTOR pathway regulates a oligomer induced neuronal cell cycle events. Mol Neurodegener 4: 1–18. doi: 10.1186/1750-1326-4-1
[66]	Varvel NH, Bhaskar K, Patil AR, et al. (2008) Aβ oligomers induce neuronal cell cycle events in Alzheimer's disease. J Neurosci 28: 10786–10793. doi: 10.1523/JNEUROSCI.2441-08.2008
[67]	Kim HJ, Chae SC, Lee DK, et al. (2003) Selective neuronal degeneration induced by soluble oligomeric amyloid β protein. FASEB J 17: 118–120. doi: 10.1096/fj.01-0987fje
[68]	Roher AE, Lowenson JD, Clarke S, et al. (1993) β-Amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease. P Natl Acad Sci USA 90: 10836. doi: 10.1073/pnas.90.22.10836
[69]	Näslund J, Schierhorn A, Hellman U, et al. (1994) Relative abundance of Alzheimer Aβ amyloid peptide variants in Alzheimer disease and normal aging. P Natl Acad Sci USA 91: 8378. doi: 10.1073/pnas.91.18.8378
[70]	Vandersteen A, Hubin E, Sarroukh R, et al. (2012) A comparative analysis of the aggregation behavior of amyloid-β peptide variants. FEBS Lett 586: 4088–4093. doi: 10.1016/j.febslet.2012.10.022
[71]	Barrow CJ, Yasuda A, Kenny PTM, et al. (1992) Solution conformations and aggregational properties of synthetic amyloid β-peptides of Alzheimer's disease: Analysis of circular dichroism spectra. J Mol Biol 225: 1075–1093. doi: 10.1016/0022-2836(92)90106-T
[72]	Barrow CJ, Zagorski MG (1991) Solution structures of β peptide and its constituent fragments: Relation to amyloid deposition. Science 253: 179–182. doi: 10.1126/science.1853202
[73]	Inouye H, Fraser PE, Kirschner DA (1993) Structure of β-crystallite assemblies formed by Alzheimer β-amyloid protein analogs-analysis by x-ray diffraction. Biophys J 64: 502–519. doi: 10.1016/S0006-3495(93)81393-6
[74]	Torok M, Milton S, Kayed R, et al. (2002) Structural and dynamic features of Alzheimer's Aβ peptide in amyloid fibrils studied by site-directed spin labeling. J Biol Chem 277: 40810–40815. doi: 10.1074/jbc.M205659200
[75]	Antzutkin ON, Balbach JJ, Leapman RD, et al. (2000) Multiple quantum solid-state NMR indicates a parallel, not antiparallel, organization of β-sheets in Alzheimer's β-amyloid fibrils. P Natl Acad Sci USA 97: 13045–13050. doi: 10.1073/pnas.230315097
[76]	Petkova AT, Leapman RD, Guo ZH, et al. (2005) Self-propagating, molecular-level polymorphism in Alzheimer's β-amyloid fibrils. Science 307: 262–265. doi: 10.1126/science.1105850
[77]	Tycko R (2006) Solid-state NMR as a probe of amyloid structure. Protein Peptide Lett 13: 229–234. doi: 10.2174/092986606775338470
[78]	Pastor MT, Kuemmerer N, Schubert V, et al. (2008) Amyloid toxicity is independent of polypeptide sequence, length and chirality. J Mol Biol 375: 695–707. doi: 10.1016/j.jmb.2007.08.012
[79]	Chiti F, Dobson CM (2006) Protein misfolding, functional amyloid, and human disease. Annu Rev Biochem 75: 333–366. doi: 10.1146/annurev.biochem.75.101304.123901
[80]	Xue WF, Homans SW, Radford SE (2008) Systematic analysis of nucleation-dependent polymerization reveals new insights into the mechanism of amyloid self-assembly. Proc Natl Acad Sci USA 105: 8926–8931. doi: 10.1073/pnas.0711664105
[81]	Murphy R (2007) Kinetics of amyloid formation and membrane interaction with amyloidogenic proteins. BBA-Biomembranes 1768: 1923–1934. doi: 10.1016/j.bbamem.2006.12.014
[82]	Ghosh P, Vaidya A, Kumar A, et al. (2016) Determination of critical nucleation number for a single nucleation amyloid-β aggregation model. Math Biosci 273: 70–79. doi: 10.1016/j.mbs.2015.12.004
[83]	Garai K, Sahoo B, Sengupta P, et al. (2008) Quasihomogeneous nucleation of amyloid β yields numerical bounds for the critical radius, the surface tension, and the free energy barrier for nucleus formation. J Chem Phys 128: 045102. doi: 10.1063/1.2822322
[84]	Novo M, Freire S, Al-Soufi W (2018) Critical aggregation concentration for the formation of early Amyloid-β(1-42) oligomers. Sci Rep 8: 1783. doi: 10.1038/s41598-018-19961-3
[85]	Xue C, Lin TY, Chang D, et al. (2017) Thioflavin T as an amyloid dye: Fibril quantification, optimal concentration and effect on aggregation. Roy Soc Open Sci 4: 160696. doi: 10.1098/rsos.160696
[86]	Kodali R, Wetzel R (2007) Polymorphism in the intermediates and products of amyloid assembly. Curr Opin Struc Biol 17: 48–57. doi: 10.1016/j.sbi.2007.01.007
[87]	Kodali R, Williams AD, Chemuru S, et al. (2010) Aβ(1-40) forms five distinct amyloid structures whose β-sheet contents and fibril stabilities are correlated. J Mol Biol 401: 503–517. doi: 10.1016/j.jmb.2010.06.023
[88]	Meinhardt J, Sachse C, Hortschansky P, et al. (2009) Aβ(1-40) fibril polymorphism implies diverse interaction patterns in amyloid fibrils. J Mol Biol 386: 869–877. doi: 10.1016/j.jmb.2008.11.005
[89]	Tycko R (2015) Amyloid polymorphism: Structural basis and neurobiological relevance. Neuron 86: 632–645. doi: 10.1016/j.neuron.2015.03.017
[90]	Colletier JP, Laganowsky A, Landau M, et al. (2011) Molecular basis for amyloid-β polymorphism. P Natl Acad Sci USA 108: 16938–16943. doi: 10.1073/pnas.1112600108
[91]	Crowther RA, Goedert M (2000) Abnormal Tau-containing filaments in Neurodegenerative Disease. J Struct Biol 130: 271–279. doi: 10.1006/jsbi.2000.4270
[92]	Lu JX, Qiang W, Yau WM, et al. (2013) Molecular structure of β-amyloid fibrils in Alzheimer's disease brain tissue. Cell 154: 1257–1268. doi: 10.1016/j.cell.2013.08.035
[93]	Qiang W, Yau WM, Lu JX, et al. (2017) Structural variation in amyloid-β fibrils from Alzheimer's disease clinical subtypes. Nature 541: 217–221. doi: 10.1038/nature20814
[94]	Paravastu AK, Qahwash I, Leapman RD, et al. (2009) Seeded growth of β-amyloid fibrils from Alzheimer's brain-derived fibrils produces a distinct fibril structure. P Natl Acad Sci USA 106: 7443–7448. doi: 10.1073/pnas.0812033106
[95]	Yates EA, Legleiter J (2014) Preparation protocols of Aβ(1-40) promote the formation of polymorphic aggregates and altered interactions with lipid bilayers. Biochemistry 53: 7038–7050. doi: 10.1021/bi500792f
[96]	Teplow DB (2013) On the subject of rigor in the study of amyloid β-protein assembly. Alzheimers Res Ther 5: 39. doi: 10.1186/alzrt203
[97]	Lee MC, Yu WC, Shih YH, et al. (2018) Zinc ion rapidly induces toxic, off-pathway amyloid-β oligomers distinct from amyloid-β derived diffusible ligands in Alzheimer's disease. Sci Rep 8: 1–16. doi: 10.1038/s41598-017-17765-5
[98]	Ryan DA, Narrow WC, Federoff HJ, et al. (2010) An improved method for generating consistent soluble amyloid-β oligomer preparations for in vitro neurotoxicity studies. J Neurosci Meth 190: 171–179. doi: 10.1016/j.jneumeth.2010.05.001
[99]	Barghorn S, Nimmrich V, Striebinger A, et al. (2005) Globular amyloid β-peptide1-42 oligomer-A homogenous and stable neuropathological protein in Alzheimer's disease. J Neurochem 95: 834–847. doi: 10.1111/j.1471-4159.2005.03407.x
[100]	Thibaudeau TA, Anderson RT, Smith DM (2018) A common mechanism of proteasome impairment by neurodegenerative disease-associated oligomers. Nat Commun 9: 1097. doi: 10.1038/s41467-018-03509-0
[101]	Stine WB, Dahlgren KN, Krafft GA, et al. (2003) In vitro characterization of conditions for amyloid-b peptide oligomerization and fibrillogenesis. J Biol Chem 278: 11612–11622. doi: 10.1074/jbc.M210207200
[102]	Stine WB, Jungbauer L, Yu C, et al. (2011) Preparing synthetic Aβ in different aggregation states, In: Roberson ED (editor.), Alzheimer's Disease and Frontotemporal Dementia. Methods in Molecular Biology (Methods and Protocols), Totowa, NJ: Humana Press, 13–32.
[103]	Benninger RJ, David T (1983) An improved method of preparing the amyloid β-protein for fibrillogenesis and neurotoxicity experiments. Brain Res Rev 287: 173–196.
[104]	Ryan TM, Caine J, Mertens HDT, et al. (2013) Ammonium hydroxide treatment of Aβ produces an aggregate free solution suitable for biophysical and cell culture characterization. PeerJ 1: e73. doi: 10.7717/peerj.73
[105]	Bitan G, Lomakin A, Teplow DB (2001) Amyloid β-protein oligomerization: Prenucleation interactions revealed by photo-induced cross-linking of unmodified proteins. J Biol Chem 276: 35176–35184. doi: 10.1074/jbc.M102223200
[106]	Lesne SE (2013) Breaking the code of amyloid-β oligomers. Int J Cell Biol 2013: 950783.
[107]	Sengupta U, Nilson AN, Kayed R (2016) The role of amyloid-β oligomers in toxicity, propagation, and immunotherapy. EBioMedicine 6: 42–49. doi: 10.1016/j.ebiom.2016.03.035
[108]	Benilova I, Karran E, De Strooper B (2012) The toxic Aβ oligomer and Alzheimer's disease: An emperor in need of clothes. Nat Neurosci 15: 349–357. doi: 10.1038/nn.3028
[109]	Ferreira ST, Lourenco MV, Oliveira MM, et al. (2015) Soluble amyloid-β oligomers as synaptotoxins leading to cognitive impairment in Alzheimer's disease. Front Cell Neurosci 9: 191.
[110]	Cline EN, Bicca MA, Viola KL, et al. (2018) The amyloid-β oligomer hypothesis: Beginning of the third decade. J Alzheimers Dis 64: S567–S610. doi: 10.3233/JAD-179941
[111]	Brody DL, Jiang H, Wildburger N, et al. (2017) Non-canonical soluble amyloid-β aggregates and plaque buffering: Controversies and future directions for target discovery in Alzheimer's disease. Alzheimers Res Ther 9: 62. doi: 10.1186/s13195-017-0293-3
[112]	Sherman MA, LaCroix M, Amar F, et al. (2016) Soluble conformers of Aβ and Tau alter selective proteins governing axonal transport. J Neurosci 36: 9647–9658. doi: 10.1523/JNEUROSCI.1899-16.2016
[113]	O'Malley TT, Oktaviani NA, Zhang D, et al. (2014) Aβ dimers differ from monomers in structural propensity, aggregation paths and population of synaptotoxic assemblies. Biochem J 461: 413–426. doi: 10.1042/BJ20140219
[114]	Cheng IH, Scearce-Levie K, Legleiter J, et al. (2007) Accelerating amyloid-β fibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse models. J Biol Chem 282: 23818–23828. doi: 10.1074/jbc.M701078200
[115]	Amar F, Sherman MA, Rush T, et al. (2017) The amyloid-β oligomer Aβ56 induces specific alterations in neuronal signaling that lead to tau phosphorylation and aggregation. Sci Signal* 10: eaal2021. doi: 10.1126/scisignal.aal2021
[116]	Liu P, Reed MN, Kotilinek LA, et al. (2015) Quaternary structure defines a large class of amyloid-β oligomers neutralized by sequestration. Cell Rep 11: 1760–1771. doi: 10.1016/j.celrep.2015.05.021
[117]	Knight EM, Kim SH, Kottwitz JC, et al. (2016) Effective anti-Alzheimer Aβ therapy involves depletion of specific Aβ oligomer subtypes. Neurol Neuroimmunol Neuroinflamm 3: e237. doi: 10.1212/NXI.0000000000000237
[118]	Velasco PT, Heffern MC, Sebollela A, et al. (2012) Synapse-binding subpopulations of Aβ oligomers sensitive to peptide assembly blockers and scFv antibodies. ACS Chem Neurosci 3: 972–981. doi: 10.1021/cn300122k
[119]	Ryan TM, Roberts BR, McColl G, et al. (2015) Stabilization of nontoxic Aβ-oligomers: Insights into the mechanism of action of hydroxyquinolines in Alzheimer's disease. J Neurosci 35: 2871–2884. doi: 10.1523/JNEUROSCI.2912-14.2015
[120]	Ferreira IL, Ferreiro E, Schmidt J, et al. (2015) Aβ and NMDAR activation cause mitochondrial dysfunction involving ER calcium release. Neurobiol Aging 36: 680–692. doi: 10.1016/j.neurobiolaging.2014.09.006
[121]	Barz B, Liao Q, Strodel B (2018) Pathways of amyloid-β aggregation depend on oligomer shape. J Am Chem Soc 140: 319–327. doi: 10.1021/jacs.7b10343
[122]	Brito-Moreira J, Lourenco MV, Oliveira MM, et al. (2017) Interaction of amyloid-β (Aβ) oligomers with neurexin 2 and neuroligin 1 mediates synapse damage and memory loss in mice. J Biol Chem 292: 7327–7337. doi: 10.1074/jbc.M116.761189
[123]	Figueiredo CP, Clarke JR, Ledo JH, et al. (2013) Memantine rescues transient cognitive impairment caused by high-molecular-weight Aβ oligomers but not the persistent impairment induced by low-molecular-weight oligomers. J Neurosci 33: 9626–9317. doi: 10.1523/JNEUROSCI.0482-13.2013
[124]	Upadhaya AR, Lungrin I, Yamaguchi H, et al. (2012) High-molecular weight Aβ oligomers and protofibrils are the predominant Aβ species in the native soluble protein fraction of the AD brain. J Cell Mol Med 16: 287–295. doi: 10.1111/j.1582-4934.2011.01306.x
[125]	Mc Donald JM, O'Malley TT, Liu W, et al. (2015) The aqueous phase of Alzheimer's disease brain contains assemblies built from similar to 4 and similar to 7 kDa Aβ species. Alzheimers Dement 11: 1286–1305. doi: 10.1016/j.jalz.2015.01.005
[126]	Savioz A, Giannakopoulos P, Herrmann FR, et al. (2016) A study of Aβ oligomers in the temporal cortex and cerebellum of patients with neuropathologically confirmed Alzheimer's disease compared to aged controls. Neurodegener Dis 16: 398–406. doi: 10.1159/000446283
[127]	Breydo L, Kurouski D, Rasool S, et al. (2016) Structural differences between amyloid β oligomers. Biochem Bioph Res Co 477: 700–705. doi: 10.1016/j.bbrc.2016.06.122
[128]	Watanabe-Nakayama T, Ono K, Itami M, et al. (2016) High-speed atomic force microscopy reveals structural dynamics of amyloid β(1-42) aggregates. P Natl Acad Sci USA 113: 5835–5840. doi: 10.1073/pnas.1524807113
[129]	Matsumura S, Shinoda K, Yamada M, et al. (2011) Two distinct amyloid β-protein (Aβ) assembly pathways leading to oligomers and fibrils identified by combined fluorescence correlation spectroscopy, morphology, and toxicity analyses. J Biol Chem 286: 11555–11562. doi: 10.1074/jbc.M110.181313
[130]	Miller Y, Ma B, Nussinov R (2010) Polymorphism in Alzheimer Aβ amyloid organization reflects conformational selection in a rugged energy landscape. Chem Rev 110: 4820–4838. doi: 10.1021/cr900377t
[131]	Bernstein SL, Dupuis NF, Lazo ND, et al. (2009) Amyloid-β protein oligomerization and the importance of tetramers and dodecamers in the aetiology of Alzheimer's disease. Nat Chem 1: 326–331. doi: 10.1038/nchem.247
[132]	Economou NJ, Giammona MJ, Do TD, et al. (2016) Amyloid β-protein assembly and Alzheimer's disease: Dodecamers of Aβ42, but not of Aβ40, seed fibril formation. J Am Chem Soc 138: 1772–1775. doi: 10.1021/jacs.5b11913
[133]	Shamitko-Klingensmith N, Boyd JW, Legleiter J (2016) Microtubule modification influences cellular response to amyloid-β exposure. AIMS Biophysics 3: 261–285. doi: 10.3934/biophy.2016.2.261
[134]	Yates EA, Cucco EM, Legleiter J (2011) Point mutations in Aβ induce polymorphic aggregates at liquid/solid interfaces. ACS Chem Neurosci 2: 294–307. doi: 10.1021/cn200001k
[135]	Yates EA, Owens SL, Lynch MF, et al. (2013) Specific domains of Aβ facilitate aggregation on and association with lipid bilayers. J Mol Biol 425: 1915–1933. doi: 10.1016/j.jmb.2013.03.022
[136]	Glabe CG (2008) Structural classification of toxic amyloid oligomers. J Biol Chem 283: 29639–29643. doi: 10.1074/jbc.R800016200
[137]	Chromy BA, Nowak RJ, Lambert MP, et al. (2003) Self-assembly of Aβ(1-42) into globular neurotoxins. Biochemistry 42: 12749–12760. doi: 10.1021/bi030029q
[138]	Glabe CG (2006) Common mechanisms of amyloid oligomer pathogenesis in degenerative disease. Neurobiol Aging 27: 570–575. doi: 10.1016/j.neurobiolaging.2005.04.017
[139]	Lee EB, Leng LZ, Zhang B, et al. (2006) Targeting amyloid-β peptide (Aβ) oligomers by passive immunization with a conformation-selective monoclonal antibody improves learning and memory in Aβ precursor protein (APP) transgenic mice. J Biol Chem 281: 4292–4299. doi: 10.1074/jbc.M511018200
[140]	Lambert MP, Velasco PT, Chang L, et al. (2007) Monoclonal antibodies that target pathological assemblies of Aβ. J Neurochem 100: 23–35. doi: 10.1111/j.1471-4159.2006.04157.x
[141]	Hayden EY, Conovaloff JL, Mason A, et al. (2017) Preparation of pure populations of covalently stabilized amyloid β-protein oligomers of specific sizes. Anal Biochem 518: 78–85. doi: 10.1016/j.ab.2016.10.026
[142]	Ono K, Li L, Takamura Y, et al. (2012) Phenolic compounds prevent amyloid β-protein oligomerization and synaptic dysfunction by site-specific binding. J Biol Chem 287: 14631–14643. doi: 10.1074/jbc.M111.325456
[143]	Bitan G, Kirkitadze MD, Lomakin A, et al. (2003) Amyloid β-protein (Aβ) assembly: Aβ40 and Aβ42 oligomerize through distinct pathways. P Natl Acad Sci USA 100: 330–335. doi: 10.1073/pnas.222681699
[144]	Al-Hilaly YK, Williams TL, Stewart-Parker M, et al. (2013) A central role for dityrosine crosslinking of Amyloid-β in Alzheimer's disease. Acta Neuropathol Commun 1: 83. doi: 10.1186/2051-5960-1-83
[145]	Bush AI (2013) The metal theory of Alzheimer's disease. J Alzheimers Dis 33: S277–S281.
[146]	Butterfield DA, Boyd-Kimball D (2018) Oxidative stress, amyloid-β peptide, and altered key molecular pathways in the pathogenesis and progression of Alzheimer's disease. J Alzheimers Dis 62: 1345–1367. doi: 10.3233/JAD-170543
[147]	Smith DP, Ciccotosto GD, Tew DJ, et al. (2007) Concentration dependent Cu²⁺ induced aggregation and dityrosine formation of the Alzheimer's disease amyloid-β peptide. Biochemistry 46: 2881–2891. doi: 10.1021/bi0620961
[148]	Ryan TM, Kirby N, Mertens HDT, et al. (2015) Small angle X-ray scattering analysis of Cu²⁺-induced oligomers of the Alzheimer's amyloid β peptide. Metallomics 7: 536–543. doi: 10.1039/C4MT00323C
[149]	Takano K, Endo S, Mukaiyama A, et al. (2006) Structure of amyloid β fragments in aqueous environments. FEBS J 273: 150–158. doi: 10.1111/j.1742-4658.2005.05051.x
[150]	Streltsov VA, Varghese JN, Masters CL, et al. (2011) Crystal structure of the amyloid-β p3 fragment provides a model for oligomer formation in Alzheimer's disease. J Neurosci 31: 1419–1426. doi: 10.1523/JNEUROSCI.4259-10.2011
[151]	Liu C, Sawaya MR, Cheng PN, et al. (2011) Characteristics of amyloid-related oligomers revealed by crystal structures of macrocyclic β-sheet mimics. J Am Chem Soc 133: 6736–6744. doi: 10.1021/ja200222n
[152]	Pham JD, Chim N, Goulding CW, et al. (2013) Structures of oligomers of a peptide from β-amyloid. J Am Chem Soc 135: 12460–12467. doi: 10.1021/ja4068854
[153]	Spencer RK, Li H, Nowick JS (2014) X-ray crystallographic structures of trimers and higher-order oligomeric sssemblies of a peptide derived from Aβ_17–36. J Am Chem Soc 136: 5595–5598. doi: 10.1021/ja5017409
[154]	Bhatia R, Lin H, Lal R (2000) Fresh and nonfibrillar amyloid b protein(1-42) induces rapid cellular degeneration in aged human fibroblasts: Evidence for AbP-channel-mediated cellular toxicity. FASEB 14: 1233–1243. doi: 10.1096/fasebj.14.9.1233
[155]	Lin H, Bhatia R, Lal R (2001) Amyloid b protein forms ion channels: Implications for Alzheimer's disease pathophysiology. FASEB 15: 2433–2444. doi: 10.1096/fj.01-0377com
[156]	Lin H, Zhu YJ, Lal R (1999) Amyloid-b protein (1–40) forms calcium-permeable, Zn²⁺-sensitive channel in reconstituted lipid vesicles. Biochemistry 38: 11189–11196. doi: 10.1021/bi982997c
[157]	Rhee SK, Quist AP, Lal R (1998) Amyloid b protein-(1-42) forms calcium-permeable, Zn²⁺-sensitive channel. J Biol Chem 273: 13379–13382. doi: 10.1074/jbc.273.22.13379
[158]	Parbhu A, Lin H, Thimm J, et al. (2002) Imaging real-time aggregation of amyloid β protein (1-42) by atomic force microscopy. Peptides 23: 1265–1270. doi: 10.1016/S0196-9781(02)00061-X
[159]	Legleiter J, (2011) Assessing Aβ aggregation state by atomic force microscopy, In: Roberson ED (editor.), Alzheimer's Disease and Frontotemporal Dementia: Methods and Protocols, 57–70.
[160]	Kowalewski T, Holtzman DM (1999) In situ atomic force microscopy study of Alzheimer's β-amyloid peptide on different substrates: New insights into mechanism of β-sheet formation. Proc Natl Acad Sci USA 96: 3688–3693. doi: 10.1073/pnas.96.7.3688
[161]	Hane F, Drolle E, Gaikwad R, et al. (2011) Amyloid-β aggregation on model lipid membranes: An atomic force microscopy study. J Alzheimers Dis 26: 485–494. doi: 10.3233/JAD-2011-102112
[162]	Legleiter J, Fryer JD, Holtzman DM, et al. (2011) The modulating effect of mechanical changes in lipid bilayers caused by apoE-containing lipoproteins on Aβ induced membrane disruption. ACS Chem Neurosci 2: 588–599. doi: 10.1021/cn2000475
[163]	Yip CM, Elton EA, Darabie AA, et al. (2001) Cholesterol, a modulator of membrane-associated Ab-fibrillogenesis and neurotoxicity. J Mol Biol 311: 723–734. doi: 10.1006/jmbi.2001.4881
[164]	Yip CM, McLaurin J (2001) Amyloid-b assembly: A critical step in fibrillogensis and membrane disruption. Biophys J 80: 1359–1371. doi: 10.1016/S0006-3495(01)76109-7
[165]	Pifer PM, Yates EA, Legleiter J (2011) Point mutations in Aβ result in the formation of distinct polymorphic aggregates in the presence of lipid bilayers. PLoS One 6: e16248. doi: 10.1371/journal.pone.0016248
[166]	Burke KA, Yates EA, Legleiter J (2013) Amyloid-forming proteins alter the local mechanical properties of lipid membranes. Biochemistry 52: 808–817. doi: 10.1021/bi301070v
[167]	Hane F, Tran G, Attwood S, et al. (2013) Cu²⁺ affects amyloid-β (1-42) aggregation by increasing peptide-peptide binding forces. PLoS One 8: e59005. doi: 10.1371/journal.pone.0059005
[168]	Kim BH, Palermo NY, Lovas S, et al. (2011) Single-molecule atomic force microscopy force spectroscopy study of Aβ-40 interactions. Biochemistry 50: 5154–5162. doi: 10.1021/bi200147a
[169]	Banerjee S, Sun Z, Hayden EY, et al. (2017) Nanoscale dynamics of amyloid-β42 oligomers as revealed by high-speed atomic force microscopy. ACS Nano 11: 12202–12209. doi: 10.1021/acsnano.7b05434
[170]	Yang T, Li S, Xu H, et al. (2017) Large soluble oligomers of amyloid β-protein from Alzheimer brain are far less neuroactive than the smaller oligomers to which they dissociate. J Neurosci 37: 152–163. doi: 10.1523/JNEUROSCI.1698-16.2016
[171]	Ahmed M, Davis J, Aucoin D, et al. (2010) Structural conversion of neurotoxic amyloid-β(1-42) oligomers to fibrils. Nat Struct Mol Biol 17: 561–556. doi: 10.1038/nsmb.1799
[172]	Chimon S, Shaibat MA, Jones CR, et al. (2007) Evidence of fibril-like β-sheet structures in a neurotoxic amyloid intermediate of Alzheimer's β-amyloid. Nat Struct Mol Biol 14: 1157–1164. doi: 10.1038/nsmb1345
[173]	Stroud JC, Liu C, Teng PK, et al. (2012) Toxic fibrillar oligomers of amyloid-β have cross-β structure. P Natl Acad Sci USA 109: 7717–7722. doi: 10.1073/pnas.1203193109
[174]	Gu L, Liu C, Stroud JC, et al. (2014) Antiparallel triple-strand architecture for prefibrillar Aβ42 oligomers. J Biol Chem 289: 27300–27313. doi: 10.1074/jbc.M114.569004
[175]	Teoh CL, Su D, Sahu S, et al. (2015) Chemical fluorescent probe for detection of Aβ oligomers. J Am Chem Soc 137: 13503–13509. doi: 10.1021/jacs.5b06190
[176]	Jameson LP, Dzyuba SV (2013) Aza-BODIPY: Improved synthesis and interaction with soluble Aβ1-42 oligomers. Bioorg Med Chem Lett 23: 1732–1735. doi: 10.1016/j.bmcl.2013.01.065
[177]	Ono M, Watanabe H, Kimura H, et al. (2012) BODIPY-based molecular probe for imaging of cerebral β-amyloid plaques. ACS Chem Neurosci 3: 319–324. doi: 10.1021/cn3000058
[178]	Verwilst P, Kim HR, Seo J, et al. (2017) Rational design of in vivo Tau tangle-selective near-infrared fluorophores: expanding the BODIPY universe. J Am Chem Soc 139: 13393–13403. doi: 10.1021/jacs.7b05878

Reader Comments

Your name:*

Email:*
© 2019 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)