Skip to main content

Advertisement

SpringerLink
Log in

Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis

  • Review
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Protein aggregation is common to dozens of diseases including prionoses, diabetes, Parkinson’s and Alzheimer’s. Over the past 15 years, there has been a paradigm shift in understanding the structural basis for these proteinopathies. Precedent for this shift has come from investigation of soluble Aβ oligomers (AβOs), toxins now widely regarded as instigating neuron damage leading to Alzheimer’s dementia. Toxic AβOs accumulate in AD brain and constitute long-lived alternatives to the disease-defining Aβ fibrils deposited in amyloid plaques. Key experiments using fibril-free AβO solutions demonstrated that while Aβ is essential for memory loss, the fibrillar Aβ in amyloid deposits is not the agent. The AD-like cellular pathologies induced by AβOs suggest their impact provides a unifying mechanism for AD pathogenesis, explaining why early stage disease is specific for memory and accounting for major facets of AD neuropathology. Alternative ideas for triggering mechanisms are being actively investigated. Some research favors insertion of AβOs into membrane, while other evidence supports ligand-like accumulation at particular synapses. Over a dozen candidate toxin receptors have been proposed. AβO binding triggers a redistribution of critical synaptic proteins and induces hyperactivity in metabotropic and ionotropic glutamate receptors. This leads to Ca2+ overload and instigates major facets of AD neuropathology, including tau hyperphosphorylation, insulin resistance, oxidative stress, and synapse loss. Because different species of AβOs have been identified, a remaining question is which oligomer is the major pathogenic culprit. The possibility has been raised that more than one species plays a role. Despite some key unknowns, the clinical relevance of AβOs has been established, and new studies are beginning to point to co-morbidities such as diabetes and hypercholesterolemia as etiological factors. Because pathogenic AβOs appear early in the disease, they offer appealing targets for therapeutics and diagnostics. Promising therapeutic strategies include use of CNS insulin signaling enhancers to protect against the presence of toxins and elimination of the toxins through use of highly specific AβO antibodies. An AD-dependent accumulation of AβOs in CSF suggests their potential use as biomarkers and new AβO probes are opening the door to brain imaging. Overall, current evidence indicates that Aβ oligomers provide a substantive molecular basis for the cause, treatment and diagnosis of Alzheimer’s disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12

Similar content being viewed by others

Abbreviations

Aβ:

Amyloid beta

AβO:

Amyloid beta oligomer

AD:

Alzheimer’s disease

AFM:

Atomic force microscopy

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

FAD:

Familial Alzheimer’s disease

HMW:

High molecular weight

IDP:

Intrinsically disordered proteins

LMW:

Low molecular weight

LTP:

Long-term potentiation

MAb:

Monoclonal antibody

MCI:

Mild cognitive impairment

MRI:

Magnetic resonance imaging

MW:

Molecular weight

PET:

Positron emission tomography

PrP:

Prion protein

scFv:

Single chain variable fragment

References

  1. Adolfsson O, Pihlgren M, Toni N, Varisco Y, Buccarello AL, Antoniello K, Lohmann S, Piorkowska K, Gafner V, Atwal JK, Maloney J, Chen M, Gogineni A, Weimer RM, Mortensen DL, Friesenhahn M, Ho C, Paul R, Pfeifer A, Muhs A, Watts RJ (2012) An effector-reduced anti-beta-amyloid (Abeta) antibody with unique abeta binding properties promotes neuroprotection and glial engulfment of Abeta. J Neurosci Off J Soc Neurosci 32(28):9677–9689. doi:10.1523/jneurosci.4742-11.2012

    CAS  Google Scholar 

  2. Aggarwal BB, Gupta SC, Sung B (2013) Curcumin: an orally bioavailable blocker of TNF and other pro-inflammatory biomarkers. Br J Pharmacol 169(8):1672–1692. doi:10.1111/bph.12131

    CAS  PubMed Central  PubMed  Google Scholar 

  3. Arispe N (2004) Architecture of the Alzheimer’s A beta P ion channel pore. J Membr Biol 197(1):33–48. doi:10.1007/s00232-003-0638-7

    CAS  PubMed  Google Scholar 

  4. Bartl J, Meyer A, Brendler S, Riederer P, Grunblatt E (2013) Different effects of soluble and aggregated amyloid beta42 on gene/protein expression and enzyme activity involved in insulin and APP pathways. J Neural Trans Vienna Austria 1996 120(1):113–120. doi:10.1007/s00702-012-0852-5

    CAS  Google Scholar 

  5. Benilova I, Karran E, De Strooper B (2012) The toxic Abeta oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat Neurosci 15(3):349–357. doi:10.1038/nn.3028

    CAS  PubMed  Google Scholar 

  6. Beraldo FH, Arantes CP, Santos TG, Machado CF, Roffe M, Hajj GN, Lee KS, Magalhaes AC, Caetano FA, Mancini GL, Lopes MH, Americo TA, Magdesian MH, Ferguson SS, Linden R, Prado MA, Martins VR (2011) Metabotropic glutamate receptors transduce signals for neurite outgrowth after binding of the prion protein to laminin gamma1 chain. FASEB J Off Publ Fed Am Soc Exp Biol 25(1):265–279. doi:10.1096/fj.10-161653

    CAS  Google Scholar 

  7. Bitel CL, Kasinathan C, Kaswala RH, Klein WL, Frederikse PH (2012) Amyloid-beta and tau pathology of Alzheimer’s disease induced by diabetes in a rabbit animal model. J Alzheimer’s Dis 32(2):291–305. doi:10.3233/jad-2012-120571

    CAS  Google Scholar 

  8. Bomfim TR, Forny-Germano L, Sathler LB, Brito-Moreira J, Houzel JC, Decker H, Silverman MA, Kazi H, Melo HM, McClean PL, Holscher C, Arnold SE, Talbot K, Klein WL, Munoz DP, Ferreira ST, De Felice FG (2012) An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease- associated Abeta oligomers. J Clin Investig 122(4):1339–1353. doi:10.1172/jci57256

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Boutajangout A, Wisniewski T (2014) Tau-based therapeutic approaches for Alzheimer’s disease—a mini-review. Gerontology 60(5):381–385. doi:10.1159/000358875

    CAS  PubMed  Google Scholar 

  10. Bullain SS, Corrada MM, Shah BA, Mozaffar FH, Panzenboeck M, Kawas CH (2013) Poor physical performance and dementia in the oldest old: the 90 + study. JAMA Neurol 70(1):107–113. doi:10.1001/jamaneurol.2013.583

    PubMed  Google Scholar 

  11. Butterfield DA, Castegna A, Lauderback CM, Drake J (2002) Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer’s disease brain contribute to neuronal death. Neurobiol Aging 23(5):655–664

    PubMed  Google Scholar 

  12. Canale C, Seghezza S, Vilasi S, Carrotta R, Bulone D, Diaspro A, San Biagio PL, Dante S (2013) Different effects of Alzheimer’s peptide Abeta(1–40) oligomers and fibrils on supported lipid membranes. Biophys Chem 182:23–29. doi:10.1016/j.bpc.2013.07.010

    CAS  PubMed  Google Scholar 

  13. Cattepoel S, Hanenberg M, Kulic L, Nitsch RM (2011) Chronic intranasal treatment with an anti-Abeta(30-42) scFv antibody ameliorates amyloid pathology in a transgenic mouse model of Alzheimer’s disease. PLoS One 6(4):e18296. doi:10.1371/journal.pone.0018296

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Chang L, Bakhos L, Wang Z, Venton DL, Klein WL (2003) Femtomole immunodetection of synthetic and endogenous amyloid-beta oligomers and its application to Alzheimer’s disease drug candidate screening. J Mol Neurosci MN 20(3):305–313. doi:10.1385/JMN:20:3:305

    CAS  Google Scholar 

  15. Chin J, Palop JJ, Yu GQ, Kojima N, Masliah E, Mucke L (2004) Fyn kinase modulates synaptotoxicity, but not aberrant sprouting, in human amyloid precursor protein transgenic mice. J Neurosci Off J Society Neurosci 24(19):4692–4697. doi:10.1523/jneurosci.0277-04.2004

    CAS  Google Scholar 

  16. Chromy BA, Nowak RJ, Lambert MP, Viola KL, Chang L, Velasco PT, Jones BW, Fernandez SJ, Lacor PN, Horowitz P, Finch CE, Krafft GA, Klein WL (2003) Self-assembly of Abeta(1-42) into globular neurotoxins. Biochemistry 42(44):12749–12760. doi:10.1021/bi030029q

    CAS  PubMed  Google Scholar 

  17. Cleary JP, Walsh DM, Hofmeister JJ, Shankar GM, Kuskowski MA, Selkoe DJ, Ashe KH (2005) Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. Nat Neurosci 8(1):79–84. doi:10.1038/nn1372

    CAS  PubMed  Google Scholar 

  18. Cohen SI, Linse S, Luheshi LM, Hellstrand E, White DA, Rajah L, Otzen DE, Vendruscolo M, Dobson CM, Knowles TP (2013) Proliferation of amyloid-beta42 aggregates occurs through a secondary nucleation mechanism. Proc Natl Acad Sci USA 110(24):9758–9763. doi:10.1073/pnas.1218402110

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, Arbuckle M, Callaghan M, Tsai E, Plymate SR, Green PS, Leverenz J, Cross D, Gerton B (2012) Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol 69(1):29–38. doi:10.1001/archneurol.2011.233

    PubMed Central  PubMed  Google Scholar 

  20. Dal Pra I, Chiarini A, Gui L, Chakravarthy B, Pacchiana R, Gardenal E, Whitfield JF, Armato U (2014) Do astrocytes collaborate with neurons in spreading the “infectious” Abeta and tau drivers of Alzheimer’s disease? Neurosci Rev J Bring Neurobiol Neurol Psychiatr. doi:10.1177/1073858414529828

    Google Scholar 

  21. Dalgediene I, Lasickiene R, Budvytyte R, Valincius G, Morkuniene R, Borutaite V, Zvirbliene A (2013) Immunogenic properties of amyloid beta oligomers. J Biomed Sci 20:10. doi:10.1186/1423-0127-20-10

    CAS  PubMed Central  PubMed  Google Scholar 

  22. De Felice FG, Lourenco MV, Ferreira ST (2014) How does brain insulin resistance develop in Alzheimer’s disease? Alzheimer’s Dement J Alzheimer’s Assoc 10(1 Suppl):S26–S32. doi:10.1016/j.jalz.2013.12.004

    Google Scholar 

  23. De Felice FG, Vieira MN, Bomfim TR, Decker H, Velasco PT, Lambert MP, Viola KL, Zhao WQ, Ferreira ST, Klein WL (2009) Protection of synapses against Alzheimer’s-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci USA 106(6):1971–1976. doi:10.1073/pnas.0809158106

    PubMed Central  PubMed  Google Scholar 

  24. De Felice FG, Wasilewska-Sampaio AP, Barbosa AC, Gomes FC, Klein WL, Ferreira ST (2007) Cyclic AMP enhancers and Abeta oligomerization blockers as potential therapeutic agents in Alzheimer’s disease. Curr Alzheimer Res 4(3):263–271

    PubMed  Google Scholar 

  25. De Felice FG, Wu D, Lambert MP, Fernandez SJ, Velasco PT, Lacor PN, Bigio EH, Jerecic J, Acton PJ, Shughrue PJ, Chen-Dodson E, Kinney GG, Klein WL (2008) Alzheimer’s disease-type neuronal tau hyperphosphorylation induced by A beta oligomers. Neurobiol Aging 29(9):1334–1347. doi:10.1016/j.neurobiolaging.2007.02.029

    PubMed Central  PubMed  Google Scholar 

  26. de la Monte SM (2014) Type 3 diabetes is sporadic Alzheimers disease: mini-review. Eur Neuropsychopharmacol J Eur Coll Neuropsychopharmacol. doi:10.1016/j.euroneuro.2014.06.008

    Google Scholar 

  27. de la Monte SM, Wands JR (2008) Alzheimer’s disease is type 3 diabetes-evidence reviewed. J Diabetes Sci Technol 2(6):1101–1113

    PubMed Central  PubMed  Google Scholar 

  28. Di Scala C, Troadec JD, Lelievre C, Garmy N, Fantini J, Chahinian H (2014) Mechanism of cholesterol-assisted oligomeric channel formation by a short Alzheimer beta-amyloid peptide. J Neurochem 128(1):186–195. doi:10.1111/jnc.12390

    PubMed  Google Scholar 

  29. Dodart JC, Bales KR, Gannon KS, Greene SJ, DeMattos RB, Mathis C, DeLong CA, Wu S, Wu X, Holtzman DM, Paul SM (2002) Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer’s disease model. Nat Neurosci 5(5):452–457. doi:10.1038/nn842

    CAS  PubMed  Google Scholar 

  30. Domert J, Rao SB, Agholme L, Brorsson AC, Marcusson J, Hallbeck M, Nath S (2014) Spreading of amyloid-beta peptides via neuritic cell-to-cell transfer is dependent on insufficient cellular clearance. Neurobiol Dis 65:82–92. doi:10.1016/j.nbd.2013.12.019

    CAS  PubMed  Google Scholar 

  31. Dorostkar MM, Burgold S, Filser S, Barghorn S, Schmidt B, Anumala UR, Hillen H, Klein C, Herms J (2014) Immunotherapy alleviates amyloid-associated synaptic pathology in an Alzheimer’s disease mouse model. Brain J Neurol. doi:10.1093/brain/awu280

    Google Scholar 

  32. Drolle E, Hane F, Lee B, Leonenko Z (2014) Atomic force microscopy to study molecular mechanisms of amyloid fibril formation and toxicity in Alzheimer’s disease. Drug Metab Rev 46(2):207–223. doi:10.3109/03602532.2014.882354

    CAS  PubMed  Google Scholar 

  33. Drzezga A, Lautenschlager N, Siebner H, Riemenschneider M, Willoch F, Minoshima S, Schwaiger M, Kurz A (2003) Cerebral metabolic changes accompanying conversion of mild cognitive impairment into Alzheimer’s disease: a PET follow-up study. Eur J Nucl Med Mol Imaging 30(8):1104–1113. doi:10.1007/s00259-003-1194-1

    PubMed  Google Scholar 

  34. Duran-Gonzalez J, Michi ED, Elorza B, Perez-Cordova MG, Pacheco-Otalora LF, Touhami A, Paulson P, Perry G, Murray IV, Colom LV (2013) Amyloid beta peptides modify the expression of antioxidant repair enzymes and a potassium channel in the septohippocampal system. Neurobiol Aging 34(8):2071–2076. doi:10.1016/j.neurobiolaging.2013.02.005

    CAS  PubMed  Google Scholar 

  35. Edison P, Archer HA, Hinz R, Hammers A, Pavese N, Tai YF, Hotton G, Cutler D, Fox N, Kennedy A, Rossor M, Brooks DJ (2007) Amyloid, hypometabolism, and cognition in Alzheimer disease: an [11C]PIB and [18F]FDG PET study. Neurology 68(7):501–508. doi:10.1212/01.wnl.0000244749.20056.d4

    CAS  PubMed  Google Scholar 

  36. Esparza TJ, Zhao H, Cirrito JR, Cairns NJ, Bateman RJ, Holtzman DM, Brody DL (2013) Amyloid-beta oligomerization in Alzheimer dementia versus high-pathology controls. Ann Neurol 73(1):104–119. doi:10.1002/ana.23748

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Evangelisti E, Wright D, Zampagni M, Cascella R, Fiorillo C, Bagnoli S, Relini A, Nichino D, Scartabelli T, Nacmias B, Sorbi S, Cecchi C (2013) Lipid rafts mediate amyloid-induced calcium dyshomeostasis and oxidative stress in Alzheimer’s disease. Curr Alzheimer Res 10(2):143–153

    CAS  PubMed  Google Scholar 

  38. Evangelisti E, Zampagni M, Cascella R, Becatti M, Fiorillo C, Caselli A, Bagnoli S, Nacmias B, Cecchi C (2014) Plasma membrane injury depends on bilayer lipid composition in Alzheimer’s disease. J Alzheimer Dis 41(1):289–300. doi:10.3233/jad-131406

    CAS  Google Scholar 

  39. Ferreira ST, Klein WL (2011) The Abeta oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease. Neurobiol Learn Mem 96(4):529–543. doi:10.1016/j.nlm.2011.08.003

    CAS  PubMed  Google Scholar 

  40. Ferretti MT, Bruno MA, Ducatenzeiler A, Klein WL, Cuello AC (2012) Intracellular Abeta-oligomers and early inflammation in a model of Alzheimer's disease. Neurobiol Aging 33(7):1329–1342. doi:10.1016/j.neurobiolaging.2011.01.007

    CAS  PubMed  Google Scholar 

  41. Figueiredo CP, Clarke JR, Ledo JH, Ribeiro FC, Costa CV, Melo HM, Mota-Sales AP, Saraiva LM, Klein WL, Sebollela A, De Felice FG, Ferreira ST (2013) Memantine rescues transient cognitive impairment caused by high-molecular-weight abeta oligomers but not the persistent impairment induced by low-molecular-weight oligomers. J Neurosci Off J Soc Neurosci 33(23):9626–9634. doi:10.1523/jneurosci.0482-13.2013

    CAS  Google Scholar 

  42. Frackowiak J, Zoltowska A, Wisniewski HM (1994) Non-fibrillar beta-amyloid protein is associated with smooth muscle cells of vessel walls in Alzheimer disease. J Neuropathol Exp Neurol 53(6):637–645

    CAS  PubMed  Google Scholar 

  43. Gabbita SP, Srivastava MK, Eslami P, Johnson MF, Kobritz NK, Tweedie D, Greig NH, Zemlan FP, Sharma SP, Harris-White ME (2012) Early intervention with a small molecule inhibitor for tumor necrosis factor-alpha prevents cognitive deficits in a triple transgenic mouse model of Alzheimer’s disease. J Neuroinflammation 9:99. doi:10.1186/1742-2094-9-99

    CAS  PubMed Central  PubMed  Google Scholar 

  44. Garai K, Frieden C (2013) Quantitative analysis of the time course of Abeta oligomerization and subsequent growth steps using tetramethylrhodamine-labeled Abeta. Proc Natl Acad Sci USA 110(9):3321–3326. doi:10.1073/pnas.1222478110

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Georganopoulou DG, Chang L, Nam JM, Thaxton CS, Mufson EJ, Klein WL, Mirkin CA (2005) Nanoparticle-based detection in cerebral spinal fluid of a soluble pathogenic biomarker for Alzheimer’s disease. Proc Natl Acad Sci USA 102(7):2273–2276. doi:10.1073/pnas.0409336102

    CAS  PubMed Central  PubMed  Google Scholar 

  46. Gimenez-Llort L, Rivera-Hernandez G, Marin-Argany M, Sanchez-Quesada JL, Villegas S (2013) Early intervention in the 3xTg-AD mice with an amyloid beta-antibody fragment ameliorates first hallmarks of Alzheimer disease. mAbs 5(5):665–677. doi:10.4161/mabs.25424

    PubMed Central  PubMed  Google Scholar 

  47. Gong Y, Chang L, Viola KL, Lacor PN, Lambert MP, Finch CE, Krafft GA, Klein WL (2003) Alzheimer’s disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc Natl Acad Sci USA 100(18):10417–10422. doi:10.1073/pnas.1834302100

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Gouras GK, Tampellini D, Takahashi RH, Capetillo-Zarate E (2010) Intraneuronal beta-amyloid accumulation and synapse pathology in Alzheimer’s disease. Acta Neuropathol 119(5):523–541. doi:10.1007/s00401-010-0679-9

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Goure WF, Krafft GA, Jerecic J, Hefti F (2014) Targeting the proper amyloid-beta neuronal toxins: a path forward for Alzheimer’s disease immunotherapeutics. Alzheimers Res Ther 6(4):42. doi:10.1186/alzrt272

    PubMed  Google Scholar 

  50. Griffin WS (2008) Perispinal etanercept: potential as an Alzheimer therapeutic. J Neuroinflammation 5:3. doi:10.1186/1742-2094-5-3

    PubMed Central  PubMed  Google Scholar 

  51. Gruning CS, Klinker S, Wolff M, Schneider M, Toksoz K, Klein AN, Nagel-Steger L, Willbold D, Hoyer W (2013) The off-rate of monomers dissociating from amyloid-beta protofibrils. J Biol Chem 288(52):37104–37111. doi:10.1074/jbc.M113.513432

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Gu L, Liu C, Guo Z (2013) Structural insights into Abeta42 oligomers using site-directed spin labeling. J Biol Chem 288(26):18673–18683. doi:10.1074/jbc.M113.457739

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Guillot-Sestier MV, Sunyach C, Ferreira ST, Marzolo MP, Bauer C, Thevenet A, Checler F (2012) Alpha-Secretase-derived fragment of cellular prion, N1, protects against monomeric and oligomeric amyloid beta (Abeta)-associated cell death. J Biol Chem 287(7):5021–5032. doi:10.1074/jbc.M111.323626

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Guo JL, Covell DJ, Daniels JP, Iba M, Stieber A, Zhang B, Riddle DM, Kwong LK, Xu Y, Trojanowski JQ, Lee VM (2013) Distinct alpha-synuclein strains differentially promote tau inclusions in neurons. Cell 154(1):103–117. doi:10.1016/j.cell.2013.05.057

    CAS  PubMed  Google Scholar 

  55. Guo JL, Lee VM (2011) Seeding of normal Tau by pathological Tau conformers drives pathogenesis of Alzheimer-like tangles. J Biol Chem 286(17):15317–15331. doi:10.1074/jbc.M110.209296

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Haes AJ, Chang L, Klein WL, Van Duyne RP (2005) Detection of a biomarker for Alzheimer’s disease from synthetic and clinical samples using a nanoscale optical biosensor. J Am Chem Soc 127(7):2264–2271. doi:10.1021/ja044087q

    CAS  PubMed  Google Scholar 

  57. Han X, Ma Y, Liu X, Wang L, Qi S, Zhang Q, Du Y (2012) Changes in insulin-signaling transduction pathway underlie learning/memory deficits in an Alzheimer’s disease rat model. J Neural Trans Vienna Austria 1996 119(11):1407–1416. doi:10.1007/s00702-012-0803-1

    CAS  Google Scholar 

  58. Handoko M, Grant M, Kuskowski M, Zahs KR, Wallin A, Blennow K, Ashe KH (2013) Correlation of specific amyloid-beta oligomers with tau in cerebrospinal fluid from cognitively normal older adults. JAMA Neurol 70(5):594–599. doi:10.1001/jamaneurol.2013.48

    PubMed Central  PubMed  Google Scholar 

  59. Hauser PS, Ryan RO (2013) Impact of apolipoprotein E on Alzheimer’s disease. Curr Alzheimer Res 10(8):809–817

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Hayden EY, Teplow DB (2013) Amyloid beta-protein oligomers and Alzheimer’s disease. Alzheimers Res Ther 5(6):60. doi:10.1186/alzrt226

    PubMed Central  PubMed  Google Scholar 

  61. Hefti F, Goure WF, Jerecic J, Iverson KS, Walicke PA, Krafft GA (2013) The case for soluble Abeta oligomers as a drug target in Alzheimer’s disease. Trend Pharmacol Sci 34(5):261–266. doi:10.1016/j.tips.2013.03.002

    CAS  Google Scholar 

  62. Heras-Sandoval D, Ferrera P, Arias C (2012) Amyloid-beta protein modulates insulin signaling in presynaptic terminals. Neurochem Res 37(9):1879–1885. doi:10.1007/s11064-012-0800-7

    CAS  PubMed  Google Scholar 

  63. Holtta M, Hansson O, Andreasson U, Hertze J, Minthon L, Nagga K, Andreasen N, Zetterberg H, Blennow K (2013) Evaluating amyloid-beta oligomers in cerebrospinal fluid as a biomarker for Alzheimer’s disease. PLoS One 8(6):e66381. doi:10.1371/journal.pone.0066381

    PubMed Central  PubMed  Google Scholar 

  64. Intlekofer KA, Cotman CW (2013) Exercise counteracts declining hippocampal function in aging and Alzheimer’s disease. Neurobiol Dis 57:47–55. doi:10.1016/j.nbd.2012.06.011

    CAS  PubMed  Google Scholar 

  65. Izuo N, Kume T, Sato M, Murakami K, Irie K, Izumi Y, Akaike A (2012) Toxicity in rat primary neurons through the cellular oxidative stress induced by the turn formation at positions 22 and 23 of Abeta42. ACS Chem Neurosci 3(9):674–681. doi:10.1021/cn300033k

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Izzo NJ, Staniszewski A, To L, Fa M, Teich AF, Saeed F, Wostein H, Walko T 3rd, Vaswani A, Wardius M, Syed Z, Ravenscroft J, Mozzoni K, Silky C, Rehak C, Yurko R, Finn P, Look G, Rishton G, Safferstein H, Miller M, Johanson C, Stopa E, Windisch M, Hutter-Paier B, Shamloo M, Arancio O, LeVine H 3rd, Catalano SM (2014) Alzheimer’s therapeutics targeting amyloid Beta 1-42 oligomers I: abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits. PLoS One 9(11):e111898. doi:10.1371/journal.pone.0111898

    PubMed Central  PubMed  Google Scholar 

  67. Izzo NJ, Xu J, Zeng C, Kirk MJ, Mozzoni K, Silky C, Rehak C, Yurko R, Look G, Rishton G, Safferstein H, Cruchaga C, Goate A, Cahill MA, Arancio O, Mach RH, Craven R, Head E, LeVine H 3rd, Spires-Jones TL, Catalano SM (2014) Alzheimer’s therapeutics targeting amyloid beta 1-42 oligomers ii: sigma-2/pgrmc1 receptors mediate abeta 42 oligomer binding and synaptotoxicity. PLoS One 9(11):e111899. doi:10.1371/journal.pone.0111899

    PubMed Central  PubMed  Google Scholar 

  68. Janelsins MC, Mastrangelo MA, Park KM, Sudol KL, Narrow WC, Oddo S, LaFerla FM, Callahan LM, Federoff HJ, Bowers WJ (2008) Chronic neuron-specific tumor necrosis factor-alpha expression enhances the local inflammatory environment ultimately leading to neuronal death in 3xTg-AD mice. Am J Pathol 173(6):1768–1782. doi:10.2353/ajpath.2008.080528

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Jang H, Connelly L, Arce FT, Ramachandran S, Kagan BL, Lal R, Nussinov R (2013) Mechanisms for the insertion of toxic, fibril-like beta-amyloid oligomers into the membrane. J Chem Theory Comput 9(1):822–833. doi:10.1021/ct300916f

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Jang H, Connelly L, Arce FT, Ramachandran S, Lal R, Kagan BL, Nussinov R (2013) Alzheimer’s disease: which type of amyloid-preventing drug agents to employ? Phys Chem Chem Phys 15(23):8868–8877. doi:10.1039/c3cp00017f

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Jeong JS, Ansaloni A, Mezzenga R, Lashuel HA, Dietler G (2013) Novel mechanistic insight into the molecular basis of amyloid polymorphism and secondary nucleation during amyloid formation. J Mol Biol 425(10):1765–1781. doi:10.1016/j.jmb.2013.02.005

    CAS  PubMed  Google Scholar 

  72. Johnson RD, Steel DG, Gafni A (2014) Structural evolution and membrane interactions of Alzheimer’s amyloid-beta peptide oligomers: new knowledge from single-molecule fluorescence studies. Protein Sci Publ Protein Soc 23(7):869–883. doi:10.1002/pro.2479

    CAS  Google Scholar 

  73. Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, Stefansson H, Sulem P, Gudbjartsson D, Maloney J, Hoyte K, Gustafson A, Liu Y, Lu Y, Bhangale T, Graham RR, Huttenlocher J, Bjornsdottir G, Andreassen OA, Jonsson EG, Palotie A, Behrens TW, Magnusson OT, Kong A, Thorsteinsdottir U, Watts RJ, Stefansson K (2012) A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature 488(7409):96–99. doi:10.1038/nature11283

    CAS  PubMed  Google Scholar 

  74. Kalimo H, Lalowski M, Bogdanovic N, Philipson O, Bird TD, Nochlin D, Schellenberg GD, Brundin R, Olofsson T, Soliymani R, Baumann M, Wirths O, Bayer TA, Nilsson LN, Basun H, Lannfelt L, Ingelsson M (2013) The Arctic AbetaPP mutation leads to Alzheimer’s disease pathology with highly variable topographic deposition of differentially truncated Abeta. Acta Neuropathol Commun 1(1):60. doi:10.1186/2051-5960-1-60

    PubMed Central  PubMed  Google Scholar 

  75. Kayed R, Head E, Sarsoza F, Saing T, Cotman CW, Necula M, Margol L, Wu J, Breydo L, Thompson JL, Rasool S, Gurlo T, Butler P, Glabe CG (2007) Fibril specific, conformation dependent antibodies recognize a generic epitope common to amyloid fibrils and fibrillar oligomers that is absent in prefibrillar oligomers. Mol Neurodegener 2:18. doi:10.1186/1750-1326-2-18

    PubMed Central  PubMed  Google Scholar 

  76. Kayed R, Head E, Thompson JL, McIntire TM, Milton SC, Cotman CW, Glabe CG (2003) Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science NY 300(5618):486–489. doi:10.1126/science.1079469

    CAS  Google Scholar 

  77. Kayed R, Lasagna-Reeves CA (2013) Molecular mechanisms of amyloid oligomers toxicity. J Alzheimer Dis 33(Suppl 1):S67–S78. doi:10.3233/jad-2012-129001

    Google Scholar 

  78. Kerchner GA, Boxer AL (2010) Bapineuzumab. Expert Opin Biol Ther 10(7):1121–1130. doi:10.1517/14712598.2010.493872

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Kim HG, Moon M, Choi JG, Park G, Kim AJ, Hur J, Lee KT, Oh MS (2014) Donepezil inhibits the amyloid-beta oligomer-induced microglial activation in vitro and in vivo. Neurotoxicology 40:23–32. doi:10.1016/j.neuro.2013.10.004

    CAS  PubMed  Google Scholar 

  80. Kim HJ, Chae SC, Lee DK, Chromy B, Lee SC, Park YC, Klein WL, Krafft GA, Hong ST (2003) Selective neuronal degeneration induced by soluble oligomeric amyloid beta protein. FASEB J Off Publ Fed Am Soc Exp Biol 17(1):118–120. doi:10.1096/fj.01-0987fje

    CAS  Google Scholar 

  81. Klein WL (2013) Synaptotoxic amyloid-beta oligomers: a molecular basis for the cause, diagnosis, and treatment of Alzheimer’s disease? J Alzheimer Dis 33(Suppl 1):S49–S65. doi:10.3233/jad-2012-129039

    Google Scholar 

  82. Klein WL, Krafft GA, Finch CE (2001) Targeting small Abeta oligomers: the solution to an Alzheimer’s disease conundrum? Trends Neurosci 24(4):219–224

    CAS  PubMed  Google Scholar 

  83. Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, Bergstrom M, Savitcheva I, Huang GF, Estrada S, Ausen B, Debnath ML, Barletta J, Price JC, Sandell J, Lopresti BJ, Wall A, Koivisto P, Antoni G, Mathis CA, Langstrom B (2004) Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 55(3):306–319. doi:10.1002/ana.20009

    CAS  PubMed  Google Scholar 

  84. Klyubin I, Cullen WK, Hu NW, Rowan MJ (2012) Alzheimer’s disease Abeta assemblies mediating rapid disruption of synaptic plasticity and memory. Mol Brain 5:25. doi:10.1186/1756-6606-5-25

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Kodali R, Wetzel R (2007) Polymorphism in the intermediates and products of amyloid assembly. Curr Opin Struct Biol 17(1):48–57. doi:10.1016/j.sbi.2007.01.007

    CAS  PubMed  Google Scholar 

  86. Koffie RM, Hyman BT, Spires-Jones TL (2011) Alzheimer’s disease: synapses gone cold. Mol Neurodegener 6(1):63. doi:10.1186/1750-1326-6-63

    PubMed Central  PubMed  Google Scholar 

  87. Koffie RM, Meyer-Luehmann M, Hashimoto T, Adams KW, Mielke ML, Garcia-Alloza M, Micheva KD, Smith SJ, Kim ML, Lee VM, Hyman BT, Spires-Jones TL (2009) Oligomeric amyloid beta associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Proc Natl Acad Sci USA 106(10):4012–4017. doi:10.1073/pnas.0811698106

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Kovacs GG, Breydo L, Green R, Kis V, Puska G, Lorincz P, Perju-Dumbrava L, Giera R, Pirker W, Lutz M, Lachmann I, Budka H, Uversky VN, Molnar K, Laszlo L (2014) Intracellular processing of disease-associated alpha-synuclein in the human brain suggests prion-like cell-to-cell spread. Neurobiol Dis 69:76–92. doi:10.1016/j.nbd.2014.05.020

    CAS  PubMed  Google Scholar 

  89. Kumar A, Paslay LC, Lyons D, Morgan SE, Correia JJ, Rangachari V (2012) Specific soluble oligomers of amyloid-beta peptide undergo replication and form non-fibrillar aggregates in interfacial environments. J Biol Chem 287(25):21253–21264. doi:10.1074/jbc.M112.355156

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Kuszczyk MA, Sanchez S, Pankiewicz J, Kim J, Duszczyk M, Guridi M, Asuni AA, Sullivan PM, Holtzman DM, Sadowski MJ (2013) Blocking the interaction between apolipoprotein E and Abeta reduces intraneuronal accumulation of Abeta and inhibits synaptic degeneration. Am J Pathol 182(5):1750–1768. doi:10.1016/j.ajpath.2013.01.034

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Lacor PN, Buniel MC, Chang L, Fernandez SJ, Gong Y, Viola KL, Lambert MP, Velasco PT, Bigio EH, Finch CE, Krafft GA, Klein WL (2004) Synaptic targeting by Alzheimer’s-related amyloid beta oligomers. J Neurosci Off J Soc Neurosci 24(45):10191–10200. doi:10.1523/jneurosci.3432-04.2004

    CAS  Google Scholar 

  92. Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, Viola KL, Klein WL (2007) Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci Off J Soc Neurosci 27(4):796–807. doi:10.1523/jneurosci.3501-06.2007

    CAS  Google Scholar 

  93. Ladiwala AR, Litt J, Kane RS, Aucoin DS, Smith SO, Ranjan S, Davis J, Van Nostrand WE, Tessier PM (2012) Conformational differences between two amyloid beta oligomers of similar size and dissimilar toxicity. J Biol Chem 287(29):24765–24773. doi:10.1074/jbc.M111.329763

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Laganowsky A, Liu C, Sawaya MR, Whitelegge JP, Park J, Zhao M, Pensalfini A, Soriaga AB, Landau M, Teng PK, Cascio D, Glabe C, Eisenberg D (2012) Atomic view of a toxic amyloid small oligomer. Sci NY 335(6073):1228–1231. doi:10.1126/science.1213151

    CAS  Google Scholar 

  95. Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, Klein WL (1998) Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA 95(11):6448–6453

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Lambert MP, Velasco PT, Chang L, Viola KL, Fernandez S, Lacor PN, Khuon D, Gong Y, Bigio EH, Shaw P, De Felice FG, Krafft GA, Klein WL (2007) Monoclonal antibodies that target pathological assemblies of Abeta. J Neurochem 100(1):23–35. doi:10.1111/j.1471-4159.2006.04157.x

    CAS  PubMed  Google Scholar 

  97. Lambert MP, Viola KL, Chromy BA, Chang L, Morgan TE, Yu J, Venton DL, Krafft GA, Finch CE, Klein WL (2001) Vaccination with soluble Abeta oligomers generates toxicity-neutralizing antibodies. J Neurochem 79(3):595–605

    CAS  PubMed  Google Scholar 

  98. Lannfelt L, Moller C, Basun H, Osswald G, Sehlin D, Satlin A, Logovinsky V, Gellerfors P (2014) Perspectives on future Alzheimer therapies: amyloid-beta protofibrils—a new target for immunotherapy with BAN2401 in Alzheimer’s disease. Alzheimers Res Ther 6(2):16. doi:10.1186/alzrt246

    PubMed  Google Scholar 

  99. Lasagna-Reeves CA, Glabe CG, Kayed R (2011) Amyloid-beta annular protofibrils evade fibrillar fate in Alzheimer disease brain. J Biol Chem 286(25):22122–22130. doi:10.1074/jbc.M111.236257

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Lauren J (2014) Cellular prion protein as a therapeutic target in Alzheimer’s disease. J Alzheimer Dis 38(2):227–244. doi:10.3233/jad-130950

    CAS  Google Scholar 

  101. Lauren J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM (2009) Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature 457(7233):1128–1132. doi:10.1038/nature07761

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Lee EB, Leng LZ, Zhang B, Kwong L, Trojanowski JQ, Abel T, Lee VM (2006) Targeting amyloid-beta peptide (Abeta) oligomers by passive immunization with a conformation-selective monoclonal antibody improves learning and memory in Abeta precursor protein (APP) transgenic mice. J Biol Chem 281(7):4292–4299. doi:10.1074/jbc.M511018200

    CAS  PubMed  Google Scholar 

  103. Lee M, Guo JP, Schwab C, McGeer EG, McGeer PL (2012) Selective inhibition of the membrane attack complex of complement by low molecular weight components of the aurin tricarboxylic acid synthetic complex. Neurobiol Aging 33(10):2237–2246. doi:10.1016/j.neurobiolaging.2011.12.005

    CAS  PubMed  Google Scholar 

  104. Lee SH, Kim Y, Kim HY, Kim YH, Kim MS, Kong JY, Lee MH, Kim DJ, Ahn YG (2014) Aminostyrylbenzofuran directly reduces oligomeric amyloid-beta and reverses cognitive deficits in Alzheimer transgenic mice. PLoS One 9(4):e95733. doi:10.1371/journal.pone.0095733

    PubMed Central  PubMed  Google Scholar 

  105. Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH (2006) A specific amyloid-beta protein assembly in the brain impairs memory. Nature 440(7082):352–357. doi:10.1038/nature04533

    CAS  PubMed  Google Scholar 

  106. LeVine H 3rd (2004) Alzheimer’s beta-peptide oligomer formation at physiologic concentrations. Anal Biochem 335(1):81–90. doi:10.1016/j.ab.2004.08.014

    CAS  PubMed  Google Scholar 

  107. Li S, Jin M, Zhang D, Yang T, Koeglsperger T, Fu H, Selkoe DJ (2013) Environmental novelty activates beta2-adrenergic signaling to prevent the impairment of hippocampal LTP by Abeta oligomers. Neuron 77(5):929–941. doi:10.1016/j.neuron.2012.12.040

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Liu-Seifert H, Siemers E, Sundell K, Price K, Han B, Selzler K, Aisen P, Cummings J, Raskin J, Mohs R (2014) Cognitive and functional decline and their relationship in patients with mild Alzheimer’s dementia. J Alzheimer Dis. doi:10.3233/jad-140792

    Google Scholar 

  109. Liu C, Zhao M, Jiang L, Cheng PN, Park J, Sawaya MR, Pensalfini A, Gou D, Berk AJ, Glabe CG, Nowick J, Eisenberg D (2012) Out-of-register beta-sheets suggest a pathway to toxic amyloid aggregates. Proc Natl Acad Sci USA 109(51):20913–20918. doi:10.1073/pnas.1218792109

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Lorenzen N, Nielsen SB, Buell AK, Kaspersen JD, Arosio P, Vad BS, Paslawski W, Christiansen G, Valnickova-Hansen Z, Andreasen M, Enghild JJ, Pedersen JS, Dobson CM, Knowles TP, Otzen DE (2014) The role of stable alpha-synuclein oligomers in the molecular events underlying amyloid formation. J Am Chem Soc 136(10):3859–3868. doi:10.1021/ja411577t

    CAS  PubMed  Google Scholar 

  111. Lourenco MV, Clarke JR, Frozza RL, Bomfim TR, Forny-Germano L, Batista AF, Sathler LB, Brito-Moreira J, Amaral OB, Silva CA, Freitas-Correa L, Espirito-Santo S, Campello-Costa P, Houzel JC, Klein WL, Holscher C, Carvalheira JB, Silva AM, Velloso LA, Munoz DP, Ferreira ST, De Felice FG (2013) TNF-alpha mediates PKR-dependent memory impairment and brain IRS-1 inhibition induced by Alzheimer’s beta-amyloid oligomers in mice and monkeys. Cell Metab 18(6):831–843. doi:10.1016/j.cmet.2013.11.002

    CAS  PubMed  Google Scholar 

  112. Maesako M, Uemura K, Iwata A, Kubota M, Watanabe K, Uemura M, Noda Y, Asada-Utsugi M, Kihara T, Takahashi R, Shimohama S, Kinoshita A (2013) Continuation of exercise is necessary to inhibit high fat diet-induced beta-amyloid deposition and memory deficit in amyloid precursor protein transgenic mice. PLoS One 8(9):e72796. doi:10.1371/journal.pone.0072796

    CAS  PubMed Central  PubMed  Google Scholar 

  113. Magnusson K, Sehlin D, Syvanen S, Svedberg MM, Philipson O, Soderberg L, Tegerstedt K, Holmquist M, Gellerfors P, Tolmachev V, Antoni G, Lannfelt L, Hall H, Nilsson LN (2013) Specific uptake of an amyloid-beta protofibril-binding antibody-tracer in AbetaPP transgenic mouse brain. J Alzheimer Dis 37(1):29–40. doi:10.3233/jad-130029

    CAS  Google Scholar 

  114. Mainardi M, Di Garbo A, Caleo M, Berardi N, Sale A, Maffei L (2014) Environmental enrichment strengthens corticocortical interactions and reduces amyloid-beta oligomers in aged mice. Front Aging Neurosci 6:1. doi:10.3389/fnagi.2014.00001

    PubMed Central  PubMed  Google Scholar 

  115. Matsubara E, Takamura A, Okamoto Y, Oono H, Nakata T, Wakasaya Y, Kawarabayashi T, Shoji M (2013) Disease modifying therapies for Alzheimer’s disease targeting Abeta oligomers: implications for therapeutic mechanisms. Biomed Resh Int 2013:984041. doi:10.1155/2013/984041

    Google Scholar 

  116. McAlpine FE, Lee JK, Harms AS, Ruhn KA, Blurton-Jones M, Hong J, Das P, Golde TE, LaFerla FM, Oddo S, Blesch A, Tansey MG (2009) Inhibition of soluble TNF signaling in a mouse model of Alzheimer’s disease prevents pre-plaque amyloid-associated neuropathology. Neurobiol Dis 34(1):163–177

    CAS  PubMed Central  PubMed  Google Scholar 

  117. McClean PL, Holscher C (2014) Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged APP/PS1 mice, a model of Alzheimer’s disease. Neuropharmacology 76(Pt A):57–67. doi:10.1016/j.neuropharm.2013.08.005

    CAS  PubMed  Google Scholar 

  118. McLean D, Cooke MJ, Wang Y, Green D, Fraser PE, George-Hyslop PS, Shoichet MS (2012) Anti-amyloid-beta-mediated positron emission tomography imaging in Alzheimer’s disease mouse brains. PLoS One 7(12):e51958. doi:10.1371/journal.pone.0051958

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Moon M, Kim HG, Choi JG, Oh H, Lee PK, Ha SK, Kim SY, Park Y, Huh Y, Oh MS (2014) 6-Shogaol, an active constituent of ginger, attenuates neuroinflammation and cognitive deficits in animal models of dementia. Biochem Biophys Res Commun 449(1):8–13. doi:10.1016/j.bbrc.2014.04.121

    CAS  PubMed  Google Scholar 

  120. Morkuniene R, Zvirbliene A, Dalgediene I, Cizas P, Jankeviciute S, Baliutyte G, Jokubka R, Jankunec M, Valincius G, Borutaite V (2013) Antibodies bound to Abeta oligomers potentiate the neurotoxicity of Abeta by activating microglia. J Neurochem 126(5):604–615. doi:10.1111/jnc.12332

    CAS  PubMed  Google Scholar 

  121. Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, Hu K, Kholodenko D, Johnson-Wood K, McConlogue L (2000) High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 20(11):4050–4058

    CAS  PubMed  Google Scholar 

  122. Mucke L, Selkoe DJ (2012) Neurotoxicity of amyloid beta-protein: synaptic and network dysfunction. Cold Spring Harb Perspect Med 2(7):a006338. doi:10.1101/cshperspect.a006338

    PubMed Central  PubMed  Google Scholar 

  123. Mufson EJ, Ward S, Binder L (2014) Prefibrillar tau oligomers in mild cognitive impairment and Alzheimer’s disease. Neuro-degener Dis 13(2–3):151–153. doi:10.1159/000353687

    CAS  Google Scholar 

  124. Murakami K (2014) Conformation-specific antibodies to target amyloid beta oligomers and their application to immunotherapy for Alzheimer’s disease. Biosci Biotechnol Biochem 78(8):1293–1305. doi:10.1080/09168451.2014.940275

    CAS  PubMed  Google Scholar 

  125. Narayan P, Ganzinger KA, McColl J, Weimann L, Meehan S, Qamar S, Carver JA, Wilson MR, St George-Hyslop P, Dobson CM, Klenerman D (2013) Single molecule characterization of the interactions between amyloid-beta peptides and the membranes of hippocampal cells. J Am Chem Soc 135(4):1491–1498. doi:10.1021/ja3103567

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Narayan P, Holmstrom KM, Kim DH, Whitcomb DJ, Wilson MR, St George-Hyslop P, Wood NW, Dobson CM, Cho K, Abramov AY, Klenerman D (2014) Rare individual amyloid-beta oligomers act on astrocytes to initiate neuronal damage. Biochemistry 53(15):2442–2453. doi:10.1021/bi401606f

    CAS  PubMed Central  PubMed  Google Scholar 

  127. Nath S, Agholme L, Kurudenkandy FR, Granseth B, Marcusson J, Hallbeck M (2012) Spreading of neurodegenerative pathology via neuron-to-neuron transmission of beta-amyloid. J Neurosci Off J Soc Neurosci 32(26):8767–8777. doi:10.1523/jneurosci.0615-12.2012

    CAS  Google Scholar 

  128. Nigh AB, Vahedi S, Davis EG, Weintraub S, Bigio EH, Klein WL, Geula C (2014) Intracellular Amyloid-beta in cholinergic neurons. Brain J Neurol: In Press

  129. Nussbaum JM, Schilling S, Cynis H, Silva A, Swanson E, Wangsanut T, Tayler K, Wiltgen B, Hatami A, Ronicke R, Reymann K, Hutter-Paier B, Alexandru A, Jagla W, Graubner S, Glabe CG, Demuth HU, Bloom GS (2012) Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-beta. Nature 485(7400):651–655. doi:10.1038/nature11060

    CAS  PubMed Central  PubMed  Google Scholar 

  130. Nyborg AC, Moll JR, Wegrzyn RD, Havas D, Hutter-Paier B, Feuerstein GG, Rudolph AS (2013) In vivo and ex vivo imaging of amyloid-beta cascade aggregates with a Pronucleon peptide. J Alzheimer Dis 34(4):957–967. doi:10.3233/jad-122107

    CAS  Google Scholar 

  131. Oda T, Pasinetti GM, Osterburg HH, Anderson C, Johnson SA, Finch CE (1994) Purification and characterization of brain clusterin. Biochem Biophys Res Commun 204(3):1131–1136. doi:10.1006/bbrc.1994.2580

    CAS  PubMed  Google Scholar 

  132. Oddo S, Caccamo A, Tran L, Lambert MP, Glabe CG, Klein WL, LaFerla FM (2006) Temporal profile of amyloid-beta (Abeta) oligomerization in an in vivo model of Alzheimer disease. A link between Abeta and tau pathology. J Biol Chem 281(3):1599–1604. doi:10.1074/jbc.M507892200

    CAS  PubMed  Google Scholar 

  133. Olanow CW, Brundin P (2013) Parkinson’s disease and alpha synuclein: is Parkinson’s disease a prion-like disorder? Mov Disord Off J Mov Disorder Soc 28(1):31–40. doi:10.1002/mds.25373

    CAS  Google Scholar 

  134. Ono K, Takahashi R, Ikeda T, Yamada M (2012) Cross-seeding effects of amyloid beta-protein and alpha-synuclein. J Neurochem 122(5):883–890. doi:10.1111/j.1471-4159.2012.07847.x

    CAS  PubMed  Google Scholar 

  135. Pearson-Leary J, McNay EC (2012) Intrahippocampal administration of amyloid-beta(1-42) oligomers acutely impairs spatial working memory, insulin signaling, and hippocampal metabolism. J Alzheimer Dis 30(2):413–422. doi:10.3233/jad-2012-112192

    CAS  Google Scholar 

  136. Peng S, Garzon DJ, Marchese M, Klein W, Ginsberg SD, Francis BM, Mount HT, Mufson EJ, Salehi A, Fahnestock M (2009) Decreased brain-derived neurotrophic factor depends on amyloid aggregation state in transgenic mouse models of Alzheimer’s disease. J Neurosci Off J Socr Neurosci 29(29):9321–9329. doi:10.1523/JNEUROSCI.4736-08.2009

    CAS  Google Scholar 

  137. Peters C, Fernandez-Perez EJ, Burgos CF, Espinoza MP, Castillo C, Urrutia JC, Streltsov VA, Opazo C, Aguayo LG (2013) Inhibition of amyloid beta-induced synaptotoxicity by a pentapeptide derived from the glycine zipper region of the neurotoxic peptide. Neurobiol Aging 34(12):2805–2814. doi:10.1016/j.neurobiolaging.2013.06.001

    CAS  PubMed  Google Scholar 

  138. Pitt J, Roth W, Lacor P, Smith AB 3rd, Blankenship M, Velasco P, De Felice F, Breslin P, Klein WL (2009) Alzheimer’s-associated Abeta oligomers show altered structure, immunoreactivity and synaptotoxicity with low doses of oleocanthal. Toxicol Appl Pharmacol 240(2):189–197. doi:10.1016/j.taap.2009.07.018

    CAS  PubMed Central  PubMed  Google Scholar 

  139. Pozueta J, Lefort R, Shelanski ML (2013) Synaptic changes in Alzheimer’s disease and its models. Neuroscience 251:51–65. doi:10.1016/j.neuroscience.2012.05.050

    CAS  PubMed  Google Scholar 

  140. Prangkio P, Yusko EC, Sept D, Yang J, Mayer M (2012) Multivariate analyses of amyloid-beta oligomer populations indicate a connection between pore formation and cytotoxicity. PLoS One 7(10):e47261. doi:10.1371/journal.pone.0047261

    CAS  PubMed Central  PubMed  Google Scholar 

  141. Purro SA, Dickins EM, Salinas PC (2012) The secreted Wnt antagonist Dickkopf-1 is required for amyloid beta-mediated synaptic loss. J Neurosci Off J Soc Neurosci 32(10):3492–3498. doi:10.1523/jneurosci.4562-11.2012

    CAS  Google Scholar 

  142. Rasool S, Martinez-Coria H, Wu JW, LaFerla F, Glabe CG (2013) Systemic vaccination with anti-oligomeric monoclonal antibodies improves cognitive function by reducing Abeta deposition and tau pathology in 3xTg-AD mice. J Neurochem 126(4):473–482. doi:10.1111/jnc.12305

    CAS  PubMed Central  PubMed  Google Scholar 

  143. Renner M, Lacor PN, Velasco PT, Xu J, Contractor A, Klein WL, Triller A (2010) Deleterious effects of amyloid beta oligomers acting as an extracellular scaffold for mGluR5. Neuron 66(5):739–754. doi:10.1016/j.neuron.2010.04.029

    CAS  PubMed Central  PubMed  Google Scholar 

  144. Resende R, Marques SC, Ferreiro E, Simoes I, Oliveira CR, Pereira CM (2013) Effect of alpha-synuclein on amyloid beta-induced toxicity: relevance to Lewy body variant of Alzheimer disease. Neurochem Res 38(4):797–806. doi:10.1007/s11064-013-0982-7

    CAS  PubMed  Google Scholar 

  145. Richman M, Wilk S, Chemerovski M, Warmlander SK, Wahlstrom A, Graslund A, Rahimipour S (2013) In vitro and mechanistic studies of an antiamyloidogenic self-assembled cyclic D, L-alpha-peptide architecture. J Am Chem Soc 135(9):3474–3484. doi:10.1021/ja310064v

    CAS  PubMed  Google Scholar 

  146. Ringman JM, Tomic JL, Coppola G, Elashoff D, Gylys KH, Glabe CG (2012) Conformation-dependent oligomers in cerebrospinal fluid of presymptomatic familial Alzheimer’s disease mutation carriers. Dement Geriatr Cognit Disord Extra 2(1):652–657. doi:10.1159/000345771

    Google Scholar 

  147. Robinson R (2012) MRI probe for amyloid-beta oligomers offers potential advantages for detecting Alzheimer’s disease. Neurol Today 12(24):20–22. doi:10.1097/01.NT.0000425719.88852.88

    Google Scholar 

  148. Rosenblum WI (2014) Why Alzheimer trials fail: removing soluble oligomeric beta amyloid is essential, inconsistent, and difficult. Neurobiol Aging 35(5):969–974. doi:10.1016/j.neurobiolaging.2013.10.085

    CAS  PubMed  Google Scholar 

  149. Roychaudhuri R, Lomakin A, Bernstein S, Zheng X, Condron MM, Benedek GB, Bowers M, Teplow DB (2014) Gly25-Ser26 amyloid beta-protein structural isomorphs produce distinct Abeta42 conformational dynamics and assembly characteristics. J Mol Biol 426(13):2422–2441. doi:10.1016/j.jmb.2014.04.004

    CAS  PubMed  Google Scholar 

  150. Roychaudhuri R, Yang M, Deshpande A, Cole GM, Frautschy S, Lomakin A, Benedek GB, Teplow DB (2013) C-terminal turn stability determines assembly differences between Abeta40 and Abeta42. J Mol Biol 425(2):292–308. doi:10.1016/j.jmb.2012.11.006

    CAS  PubMed Central  PubMed  Google Scholar 

  151. Santuccione A, Sytnyk V, Leshchyns’ka I, Schachner M (2005) Prion protein recruits its neuronal receptor NCAM to lipid rafts to activate p59fyn and to enhance neurite outgrowth. J Cell Biol 169(2):341–354. doi:10.1083/jcb.200409127

    CAS  PubMed Central  PubMed  Google Scholar 

  152. Sarkar B, Das AK, Maiti S (2013) Thermodynamically stable amyloid-beta monomers have much lower membrane affinity than the small oligomers. Front Physiol 4:84. doi:10.3389/fphys.2013.00084

    PubMed Central  PubMed  Google Scholar 

  153. Sarkar B, Mithu VS, Chandra B, Mandal A, Chandrakesan M, Bhowmik D, Madhu PK, Maiti S (2014) Significant structural differences between transient amyloid-beta oligomers and less-toxic fibrils in regions known to harbor familial Alzheimer’s mutations. Angew Chem Int Ed Engl 53(27):6888–6892. doi:10.1002/anie.201402636

    CAS  PubMed  Google Scholar 

  154. Schmidt V, Carlo AS, Willnow TE (2014) Apolipoprotein E receptor pathways in Alzheimer disease. Wiley interdisciplinary reviews Systems biology and medicine 6(3):255–270. doi:10.1002/wsbm.1262

    CAS  PubMed  Google Scholar 

  155. Schnabel J (2011) Amyloid: little proteins, big clues. Nature 475(7355):S12–S14. doi:10.1038/475S12a

    CAS  PubMed  Google Scholar 

  156. Sebollela A, Freitas-Correa L, Oliveira FF, Mendes CT, Wasilewska-Sampaio AP, Camacho-Pereira J, Galina A, Brentani H, Passetti F, De Felice FG, Dias-Neto E, Ferreira ST (2010) Expression profile of rat hippocampal neurons treated with the neuroprotective compound 2,4-dinitrophenol: up-regulation of cAMP signaling genes. Neurotox Res 18(2):112–123. doi:10.1007/s12640-009-9133-y

    CAS  PubMed  Google Scholar 

  157. Selkoe DJ (2011) Resolving controversies on the path to Alzheimer’s therapeutics. Nat Med 17(9):1060–1065. doi:10.1038/nm.2460

    CAS  PubMed  Google Scholar 

  158. Siemers ER, Friedrich S, Dean RA, Gonzales CR, Farlow MR, Paul SM, Demattos RB (2010) Safety and changes in plasma and cerebrospinal fluid amyloid beta after a single administration of an amyloid beta monoclonal antibody in subjects with Alzheimer disease. Clin Neuropharmacol 33(2):67–73. doi:10.1097/WNF.0b013e3181cb577a

    CAS  PubMed  Google Scholar 

  159. Sitkiewicz E, Kloniecki M, Poznanski J, Bal W, Dadlez M (2014) Factors influencing compact-extended structure equilibrium in oligomers of abeta1-40 peptide–an ion mobility mass spectrometry study. J Mol Biol 426(15):2871–2885. doi:10.1016/j.jmb.2014.05.015

    CAS  PubMed  Google Scholar 

  160. Soejima N, Ohyagi Y, Nakamura N, Himeno E, Iinuma KM, Sakae N, Yamasaki R, Tabira T, Murakami K, Irie K, Kinoshita N, LaFerla FM, Kiyohara Y, Iwaki T, Kira J (2013) Intracellular accumulation of toxic turn amyloid-beta is associated with endoplasmic reticulum stress in Alzheimer’s disease. Curr Alzheimer Res 10(1):11–20

    CAS  PubMed  Google Scholar 

  161. Sorgjerd KM, Zako T, Sakono M, Stirling PC, Leroux MR, Saito T, Nilsson P, Sekimoto M, Saido TC, Maeda M (2013) Human prefoldin inhibits amyloid-beta (Abeta) fibrillation and contributes to formation of nontoxic Abeta aggregates. Biochemistry 52(20):3532–3542. doi:10.1021/bi301705c

    CAS  PubMed  Google Scholar 

  162. Takahashi RH, Capetillo-Zarate E, Lin MT, Milner TA, Gouras GK (2013) Accumulation of intraneuronal beta-amyloid 42 peptides is associated with early changes in microtubule-associated protein 2 in neurites and synapses. PLoS ONE 8(1):e51965. doi:10.1371/journal.pone.0051965

    CAS  PubMed Central  PubMed  Google Scholar 

  163. Takamura A, Sato Y, Watabe D, Okamoto Y, Nakata T, Kawarabayashi T, Oddo S, Laferla FM, Shoji M, Matsubara E (2012) Sortilin is required for toxic action of Abeta oligomers (AbetaOs): extracellular AbetaOs trigger apoptosis, and intraneuronal AbetaOs impair degradation pathways. Life Sci 91(23–24):1177–1186. doi:10.1016/j.lfs.2012.04.038

    CAS  PubMed  Google Scholar 

  164. Takeda S, Hashimoto T, Roe AD, Hori Y, Spires-Jones TL, Hyman BT (2013) Brain interstitial oligomeric amyloid beta increases with age and is resistant to clearance from brain in a mouse model of Alzheimer’s disease. FASEB J Off Publ Fed Am Soc Exp Biol 27(8):3239–3248. doi:10.1096/fj.13-229666

    CAS  Google Scholar 

  165. Tay WM, Huang D, Rosenberry TL, Paravastu AK (2013) The Alzheimer’s amyloid-beta(1-42) peptide forms off-pathway oligomers and fibrils that are distinguished structurally by intermolecular organization. J Mol Biol 425(14):2494–2508. doi:10.1016/j.jmb.2013.04.003

    CAS  PubMed  Google Scholar 

  166. Thapa A, Vernon BC, De la Pena K, Soliz G, Moreno HA, Lopez GP, Chi EY (2013) Membrane-mediated neuroprotection by curcumin from amyloid-beta-peptide-induced toxicity. Langmuir : the ACS journal of surfaces and colloids 29(37):11713–11723. doi:10.1021/la4020459

    CAS  Google Scholar 

  167. Torok B, Sood A, Bag S, Kulkarni A, Borkin D, Lawler E, Dasgupta S, Landge S, Abid M, Zhou W, Foster M, LeVine H 3rd, Torok M (2012) Structure-activity relationships of organofluorine inhibitors of beta-amyloid self-assembly. Chem Med Chem 7(5):910–919. doi:10.1002/cmdc.201100569

    PubMed  Google Scholar 

  168. Tsigelny IF, Sharikov Y, Kouznetsova VL, Greenberg JP, Wrasidlo W, Gonzalez T, Desplats P, Michael SE, Trejo-Morales M, Overk CR, Masliah E (2014) Structural diversity of Alzheimer’s disease amyloid-beta dimers and their role in oligomerization and fibril formation. J Alzheimer Dis 39(3):583–600. doi:10.3233/jad-131589

    CAS  Google Scholar 

  169. Tucker S, Moller C, Tegerstedt K, Lord A, Laudon H, Sjodahl J, Soderberg L, Spens E, Sahlin C, Waara ER, Satlin A, Gellerfors P, Osswald G, Lannfelt L (2014) The murine version of BAN2401 (mAb158) selectively reduces amyloid-beta protofibrils in brain and cerebrospinal fluid of tg-arcswe mice. J Alzheimer Dis. doi:10.3233/jad-140741

    Google Scholar 

  170. Um JW, Strittmatter SM (2013) Amyloid-beta induced signaling by cellular prion protein and Fyn kinase in Alzheimer disease. Prion 7(1):37–41. doi:10.4161/pri.22212

    CAS  PubMed Central  PubMed  Google Scholar 

  171. Um JW, Kaufman AC, Kostylev M, Heiss JK, Stagi M, Takahashi H, Kerrisk ME, Vortmeyer A, Wisniewski T, Koleske AJ, Gunther EC, Nygaard HB, Strittmatter SM (2013) Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer abeta oligomer bound to cellular prion protein. Neuron 79(5):887–902. doi:10.1016/j.neuron.2013.06.036

    CAS  PubMed Central  PubMed  Google Scholar 

  172. Umeda T, Tomiyama T, Kitajima E, Idomoto T, Nomura S, Lambert MP, Klein WL, Mori H (2012) Hypercholesterolemia accelerates intraneuronal accumulation of Abeta oligomers resulting in memory impairment in Alzheimer’s disease model mice. Life Sci 91(23–24):1169–1176. doi:10.1016/j.lfs.2011.12.022

    CAS  PubMed  Google Scholar 

  173. Velasco PT, Heffern MC, Sebollela A, Popova IA, Lacor PN, Lee KB, Sun X, Tiano BN, Viola KL, Eckermann AL, Meade TJ, Klein WL (2012) Synapse-binding subpopulations of Abeta oligomers sensitive to peptide assembly blockers and scFv antibodies. ACS Chem Neurosci 3(11):972–981. doi:10.1021/cn300122k

    CAS  PubMed Central  PubMed  Google Scholar 

  174. Viola KL, Sbarboro J, Sureka R, De M, Bicca MA, Wang J, Vasavada S, Satpathy S, Wu S, Joshi H, Velasco PT, MacRenaris K, Waters EA, Lu C, Phan J, Lacor P, Prasad P, Dravid VP, Klein WL (2014) Towards non-invasive diagnostic imaging of early-stage Alzheimer’s disease. Nat Nanotechnol. doi:10.1038/nnano.2014.254

    PubMed  Google Scholar 

  175. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416(6880):535–539. doi:10.1038/416535a

    CAS  PubMed  Google Scholar 

  176. Walsh DM, Tseng BP, Rydel RE, Podlisny MB, Selkoe DJ (2000) The oligomerization of amyloid beta-protein begins intracellularly in cells derived from human brain. Biochemistry 39(35):10831–10839

    CAS  PubMed  Google Scholar 

  177. Wang HW, Pasternak JF, Kuo H, Ristic H, Lambert MP, Chromy B, Viola KL, Klein WL, Stine WB, Krafft GA, Trommer BL (2002) Soluble oligomers of beta amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus. Brain Res 924(2):133–140

    CAS  PubMed  Google Scholar 

  178. Wang XP, Zhang JH, Wang YJ, Feng Y, Zhang X, Sun XX, Li JL, Du XT, Lambert MP, Yang SG, Zhao M, Klein WL, Liu RT (2009) Conformation-dependent single-chain variable fragment antibodies specifically recognize beta-amyloid oligomers. FEBS Lett 583(3):579–584. doi:10.1016/j.febslet.2008.12.064

    CAS  PubMed  Google Scholar 

  179. Watt AD, Villemagne VL, Barnham KJ (2013) Metals, membranes, and amyloid-beta oligomers: key pieces in the Alzheimer’s disease puzzle? J Alzheimer Dis 33(Suppl 1):S283–S293. doi:10.3233/jad-2012-129017

    Google Scholar 

  180. Wilcox KC, Marunde MR, Das A, Velasco PT, Kuhns B, Marty MT, Jiang H, Luan C-H, Sligar SG, Klein WL (2015) Nanoscale synaptic membrane mimetic allows unbiased high throughput screen that targets binding sites for Alzheimer’s-associated Aβ oligomers. PloS One In Press

  181. Wilhelmus MM, de Jager M, Bakker EN, Drukarch B (2014) Tissue transglutaminase in Alzheimer’s disease: involvement in pathogenesis and its potential as a therapeutic target. J Alzheimer Dis 42:S289–S303. doi:10.3233/jad-132492

    Google Scholar 

  182. Wisniewski T, Goni F (2014) Immunotherapy for Alzheimer’s disease. Biochem Pharmacol 88(4):499–507. doi:10.1016/j.bcp.2013.12.020

    CAS  PubMed  Google Scholar 

  183. Xiao C, Davis FJ, Chauhan BC, Viola KL, Lacor PN, Velasco PT, Klein WL, Chauhan NB (2013) Brain transit and ameliorative effects of intranasally delivered anti-amyloid-beta oligomer antibody in 5XFAD mice. J Alzheimer Dis 35(4):777–788. doi:10.3233/jad-122419

    Google Scholar 

  184. Xu S, Liu G, Bao X, Wu J, Li S, Zheng B, Anwyl R, Wang Q (2014) Rosiglitazone prevents amyloid-beta oligomer-induced impairment of synapse formation and plasticity via increasing dendrite and spine mitochondrial number. J Alzheimer Dis 39(2):239–251. doi:10.3233/jad-130680

    CAS  Google Scholar 

  185. Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, Chen PP, Kayed R, Glabe CG, Frautschy SA, Cole GM (2005) Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem 280(7):5892–5901. doi:10.1074/jbc.M404751200

    CAS  PubMed  Google Scholar 

  186. Yates EA, Owens SL, Lynch MF, Cucco EM, Umbaugh CS, Legleiter J (2013) Specific domains of Abeta facilitate aggregation on and association with lipid bilayers. J Mol Biol 425(11):1915–1933. doi:10.1016/j.jmb.2013.03.022

    CAS  PubMed  Google Scholar 

  187. Younan ND, Sarell CJ, Davies P, Brown DR, Viles JH (2013) The cellular prion protein traps Alzheimer’s Abeta in an oligomeric form and disassembles amyloid fibers. FASEB J Off Publ Fed Am Soc Exp Biol 27(5):1847–1858. doi:10.1096/fj.12-222588

    CAS  Google Scholar 

  188. Yuan Z, Du M, Chen Y, Dou F (2013) Construction of human Fab library and screening of a single-domain antibody of amyloid-beta 42 oligomers. Neural Regener Res 8(33):3107–3115. doi:10.3969/j.issn.1673-5374.2013.33.004

    CAS  Google Scholar 

  189. Zahs KR, Ashe KH (2013) beta-Amyloid oligomers in aging and Alzheimer’s disease. Front Aging Neurosci 5:28. doi:10.3389/fnagi.2013.00028

    CAS  PubMed Central  PubMed  Google Scholar 

  190. Zempel H, Mandelkow E (2014) Lost after translation: missorting of Tau protein and consequences for Alzheimer disease. Trend Neurosci. doi:10.1016/j.tins.2014.08.004

    PubMed  Google Scholar 

  191. Zempel H, Thies E, Mandelkow E, Mandelkow EM (2010) Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J Neurosci 30(36):11938–11950. doi:10.1523/jneurosci.2357-10.2010

    CAS  PubMed  Google Scholar 

  192. Zhang J, Peng M, Jia J (2014) Plasma Amyloid-beta Oligomers and Soluble Tumor Necrosis Factor Receptors as Potential Biomarkers of AD. Current Alzheimer research

  193. Zhang L, Yagnik G, Peng Y, Wang J, Xu HH, Hao Y, Liu YN, Zhou F (2013) Kinetic studies of inhibition of the amyloid beta (1-42) aggregation using a ferrocene-tagged beta-sheet breaker peptide. Anal Biochem 434(2):292–299. doi:10.1016/j.ab.2012.11.025

    CAS  PubMed Central  PubMed  Google Scholar 

  194. Zhao M, Wang SW, Wang YJ, Zhang R, Li YN, Su YJ, Zhou WW, Yu XL, Liu RT (2014) Pan-amyloid oligomer specific scFv antibody attenuates memory deficits and brain amyloid burden in mice with Alzheimer’s disease. Curr Alzheimer Res 11(1):69–78

    CAS  PubMed  Google Scholar 

  195. Zhao WQ, De Felice FG, Fernandez S, Chen H, Lambert MP, Quon MJ, Krafft GA, Klein WL (2008) Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J Off Publ Fed Am Soc Exp Biol 22(1):246–260. doi:10.1096/fj.06-7703com

    CAS  Google Scholar 

  196. Zheng L, Calvo-Garrido J, Hallbeck M, Hultenby K, Marcusson J, Cedazo-Minguez A, Terman A (2013) Intracellular localization of amyloid-beta peptide in SH-SY5Y neuroblastoma cells. J Alzheimer’s Dis 37(4):713–733. doi:10.3233/jad-122455

    CAS  Google Scholar 

Download references

Acknowledgments

We would like to thank Erika Cline, Henry Weiss, and Kyle Wilcox for their editorial contributions. We would also like to thank our supporters: the National Institutes of Health (AG022547, AG029460 and AG045637), Baxter Healthcare, Inc., and the Northwestern University Clinical and Translational Sciences Institute.

Author information

Authors and Affiliations

  1. Neurobiology, Northwestern University, Evanston, IL, 60208, USA

    Kirsten L. Viola & William L. Klein

  2. Cognitive Neurology and Alzheimer’s Disease Center, Northwestern University, Chicago, IL, 60611, USA

    William L. Klein

  3. Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, 60208, USA

    William L. Klein

Authors
  1. Kirsten L. Viola
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. William L. Klein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to William L. Klein.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 360 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Viola, K.L., Klein, W.L. Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis. Acta Neuropathol 129, 183–206 (2015). https://doi.org/10.1007/s00401-015-1386-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-015-1386-3

Keywords

Search

Navigation