Molecules that Disrupt Memory Circuits in Alzheimer’s Disease: The Attack on Synapses by Aβ Oligomers (ADDLs)

  • William L. Klein
  • Pascale N. Lacor
  • Fernanda G. De Felice
  • Sergio T. Ferreira
Part of the Research and Perspectives in Neurosciences book series (NEUROSCIENCE)


Individuals with early Alzheimer’s disease (AD) suffer from a selective and profound failure to form new memories. A novel molecular mechanism with implications for therapeutics and diagnostics is now emerging in which the specificity of AD for memory derives from disruption of plasticity at synapses targeted by neurologically active Aβ oligomers. We have named these oligomers “ADDLs” (for pathogenic Aβ-derived diffusible ligands). ADDLs constitute metastable alternatives to the disease-defining Aβ fibrils deposited in amyloid plaques. In AD brain, ADDLs accumulate primarily as Aβ 12-mers (∼54 kDa). The same size oligomers occur in tg-mouse AD models; in mice, these 12-mers appear concomitantly with memory failure, consistent with the ability of ADDLs to inhibit long-term potentiation (LTP) and block reversal of long-term depression (LTD). Mechanistically, ADDLs are gain-of-function ligands that bind with specificity to particular synapses, targeting synaptic spines. Binding leads to a rapid and ectopic expression of the memory-linked immediate early gene Arc. Such aberrant accumulation has been linked by others to memory dysfunction in tg-Arc mouse models. Consistent with the expected consequences of Arc overexpression, ADDLs promote loss of surface NMDA receptors and anomalous spine morphology, which are responses expected to contribute to plasticity failure and memory dysfunction. Importantly, the attack on synapses provides a putative mechanism that unifies AD memory dysfunction with major features of AD neuropathology. Recent findings show ADDL binding instigates synapse loss, AD-type tau hyperphosphorylation, and generation of reactive oxygen species (ROS). Binding sites for ADDLs are at or in the close vicinity of NMDA receptors. Antibodies against external domains of NMDA receptors reduce ADDL binding and inhibit ADDL-stimulated ROS formation. The ROS response also is inhibited by memantine, an open-channel blocker of NMDA receptors recently approved for AD therapeutics. The ability of memantine to contravene the impact of ADDLs offers a new mechanism to explain why an NMDA receptor antagonist should improve memory function in AD patients. Elimination of ADDLs by vaccines now under development could provide the first AD treatments that are truly disease-modifying. In addition to establishing a molecular mechanism of significant value for AD therapeutics and diagnostics, studies of ADDL interactions with synaptic pathways and control mechanisms ultimately may provide new insights into the extraordinary complexities of physiological synaptic information storage.


NMDA Receptor Amyloid Cascade Hypothesis Synaptic Spine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Allison DW, Chervin AS, Gelfand VI, Craig AM (2000) Postsynaptic scaffolds of excitatory and inhibitory synapses in hippocampal neurons: maintenance of core components independent of actin filaments and microtubules. J Neurosci 20:4545–4554PubMedGoogle Scholar
  2. Alzheimer A (1906) Medical file for Auguste D, including admission report and interviews conducted bu author/doctor. In: Maurer K, Volk S, Gerbaldo H (1997) Auguste D and Alzheimer’s disease. Lancet 349:1546–1549Google Scholar
  3. Bigio EH, Lambert MP, Shaw P, Lacor PN, Viola KL, Klein WL (2005) Abeta oligomers in aging and Alzheimer disease. J Neuropathol Exp Neurol 64:440Google Scholar
  4. Boutaud O, Montine TJ, Chang L, Klein WL, Oates JA (2006) PGH2-derived levuglandin adducts increase the neurotoxicity of amyloid β1-42. J Neurochem 96:917–923PubMedCrossRefGoogle Scholar
  5. Butler AE, Janson J, Soeller WC, Butler PC (2003) Increased beta-cell apoptosis prevents adaptive increase in beta-cell mass in mouse model of type 2 diabetes: evidence for role of islet amyloid formation rather than direct action of amyloid. Diabetes 52:2304–2314PubMedCrossRefGoogle Scholar
  6. Calon F, Lim GP, Yang F, Morihara T, Teter B, Ubeda O, Rostaing P, Triller A, Salem N, Jr., Ashe KH, Frautschy SA, Cole GM (2004) Docosahexaenoic acid protects from dendritic pathology in an Alzheimer’s disease mouse model. Neuron 43:633–645PubMedCrossRefGoogle Scholar
  7. Carlisle HJ, Kennedy MB (2005) Spine architecture and synaptic plasticity. Trends Neurosci 28:182–187PubMedCrossRefGoogle Scholar
  8. Chang L, Bakhos L, Wang Z, Venton DL, Klein WL (2003) Femtomole immunodetection of synthetic and endogenous Amyloid-β oligomers and its application to Alzheimer’s Disease drug candidate screening. J Mol Neurosci 20:305–313PubMedCrossRefGoogle Scholar
  9. Chen QS, Kagan BL, Hirakura Y, Xie CW (2000) Impairment of hippocampal long-term potentiation by Alzheimer amyloid beta-peptides. J Neurosci Res 60:65–72PubMedCrossRefGoogle Scholar
  10. Chin J, Palop JJ, Puolivali J, Massaro C, Bien-Ly N, Gerstein H, Scearce-Levie K, Masliah E, Mucke L (2005) Fyn kinase induces synaptic and cognitive impairments in a transgenic mouse model of Alzheimer’s disease. J Neurosci 25:9694–9703PubMedCrossRefGoogle Scholar
  11. 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 Aβ(1–42) into globular neurotoxins. Biochemistry 42:12749–12760PubMedCrossRefGoogle Scholar
  12. Conway KA, Lee SJ, Rochet JC, Ding TT, Williamson RE, Lansbury PT, Jr. (2000) Acceleration of oligomerization, not fibrillization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson’s disease: implications for pathogenesis and therapy. Proc Natl Acad Sci USA 97:571–576PubMedCrossRefGoogle Scholar
  13. Costello DA, O’Leary DM, Herron CE (2005) Agonists of peroxisome proliferator-activated receptor-gamma attenuate the Abeta-mediated impairment of LTP in the hippocampus in vitro. Neuropharmacol 49:359–366CrossRefGoogle Scholar
  14. DeFelice FG, Vieira MN, Saraiva LM, Figueroa-Villar JD, Garcia-Abreu J, Liu R, Chang L, Klein WL, Ferreira ST (2004) Targeting the neurotoxic species in Alzheimer’s disease: inhibitors of Abeta oligomerization. FASEB J 18:1366–1372CrossRefGoogle Scholar
  15. 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. Nature Neurosci 5:452–457PubMedGoogle Scholar
  16. Ferrer I, Boada RM, Sanchez Guerra ML, Rey MJ, Costa-Jussa F (2004) Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer’s disease. Brain Pathol 14:11–20PubMedGoogle Scholar
  17. Fiala JC, Spacek J, Harris KM (2002) Dendritic spine pathology: cause or consequence of neurological disorders? Brain Res Brain Res Rev 39:29–54PubMedCrossRefGoogle Scholar
  18. 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 53:637–645PubMedGoogle Scholar
  19. 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 102:2273–2276PubMedCrossRefGoogle Scholar
  20. 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 Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc Natl Acad Sci USA 100:10417–10422PubMedCrossRefGoogle Scholar
  21. Guzowski JF (2002) Insights into immediate-early gene function in hippocampal memory consolidation using antisense oligonucleotide and fluorescent imaging approaches. Hippocampus 12:86–104PubMedCrossRefGoogle Scholar
  22. Guzowski JF, Lyford GL, Stevenson GD, Houston FP, McGaugh JL, Worley PF, Barnes CA (2000) Inhibition of activity-dependent arc protein expression in the rat hippocampus impairs the maintenance of long-term potentiation and the consolidation of long-term memory. J Neurosci 20:3993–4001PubMedGoogle Scholar
  23. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356PubMedCrossRefGoogle Scholar
  24. Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256:184–185PubMedCrossRefGoogle Scholar
  25. Hoshi M, Sato M, Matsumoto S, Noguchi A, Yasutake K, Yoshida N, Sato K (2003) Spherical aggregates of beta-amyloid (amylospheroid) show high neurotoxicity and activate tau protein kinase I/glycogen synthase kinase-3beta. Proc Natl Acad Sci USA 100:6370–6375PubMedCrossRefGoogle Scholar
  26. Huang X, Atwood CS, Moir RD, Hartshorn MA, Tanzi RE, Bush AI (2004) Trace metal contamination initiates the apparent auto-aggregation, amyloidosis, and oligomerization of Alzheimer’s Abeta peptides. J Biol Inorg Chem 9:954–960PubMedCrossRefGoogle Scholar
  27. Jacobsen JS, Wu CC, Redwine JM, Comery TA, Arias R, Bowlby M, Martone R, Morrison JH, Pangalos MN, Reinhart PH, Bloom FE (2006) Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 103:5161–5166PubMedCrossRefGoogle Scholar
  28. Katzman R, Terry R, DeTeresa R, Brown T, Davies P, Fuld P, Renbing X, Peck A (1988) Clinical, pathological, and neurochemical changes in dementia: a subgroup with preserved mental status and numerous neocortical plaques. Ann Neurol 23:138–144PubMedCrossRefGoogle Scholar
  29. 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 300:486–489PubMedCrossRefGoogle Scholar
  30. Kelly MP, Deadwyler SA (2003) Experience-dependent regulation of the immediate-early gene arc differs across brain regions. J Neurosci 23:6443–6451PubMedGoogle Scholar
  31. Klein WL (2001) Aβ toxicity in Alzheimer’s Disease. In: Chesselet MF (ed) Molecular mechanisms of neurodegenerative diseases. Humana Press, Totowa, New Jersey, pp 1–49Google Scholar
  32. Klein WL (2002) Abeta toxicity in Alzheimer’s disease: globular oligomers (ADDLs) as new vaccine and drug targets. Neurochem Int 41:345PubMedCrossRefGoogle Scholar
  33. Klein WL (2005) Cytotoxic intermediates in the fibrillation pathway:Aβ oligomers in Alzheimer’s disease as a case study. In: Uversky V (ed) Protein misfolding, aggregation, and conformational diseases. Kluwer Academic/Plenum Publishers, New YorkGoogle Scholar
  34. 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 55:306–319PubMedCrossRefGoogle Scholar
  35. Klyubin I, Walsh DM, Cullen WK, Fadeeva JV, Anwyl R, Selkoe DJ, Rowan MJ (2004) Soluble Arctic amyloid beta protein inhibits hippocampal long-term potentiation in vivo. Eur J Neurosci 19:2839–2846PubMedCrossRefGoogle Scholar
  36. Klyubin I, Walsh DM, Lemere CA, Cullen WK, Shankar GM, Betts V, Spooner ET, Jiang L, Anwyl R, Selkoe DJ, Rowan MJ (2005) Amyloid beta protein immunotherapy neutralizes Abeta oligomers that disrupt synaptic plasticity in vivo. Nature Med 11:556–561PubMedCrossRefGoogle Scholar
  37. Kotilinek LA, Bacskai B, Westerman M, Kawarabayashi T, Younkin L, Hyman BT, Younkin S, Ashe KH (2002) Reversible memory loss in a mouse transgenic model of Alzheimer’s disease. J Neurosci 22:6331–6335PubMedGoogle Scholar
  38. Kuo YM, Emmerling MR, Vigo-Pelfrey C, Kasunic TC, Kirkpatrick JB, Murdoch GH, Ball MJ, Roher AE (1996) Water-soluble Abeta (N-40, N-42) oligomers in normal and Alzheimer disease brains. J Biol Chem 271:4077–4081PubMedCrossRefGoogle Scholar
  39. Lacor PN, Buniel MC, Chang L, Fernandez SJ, Gong Y, Viola KL, Lambert MP, Velasco PT, Bigio EH, Finch CE, Krafft GA, Klein WL (2004a) Synaptic targeting by Alzheimer’s-related amyloid beta oligomers. J Neurosci 24:10191–10200PubMedCrossRefGoogle Scholar
  40. Lacor PN, Buniel MC, Klein WL (2004b) ADDLs (Aβ oligomers) alter structure and function of synaptic spines. 2004 Abstract Viewer/Itinerary Planner Washington, DC: Soc Neurosci Abstract No. 218.3Google Scholar
  41. Lacor PN, Sanz-Clemente A, Viola KL, Klein WL (2005) Changes in NMDA receptor subunit 1 and 2B expression in ADDL-treated hippocampal neurons. 2005 Abstract Viewer/Itinerary Planner Washington, DC: Soc Neurosci Abstract No. 786.17Google Scholar
  42. Lacor PN, Buniel MC, Furlow PW, Sanz-Clemente A, Velasco PT, Wood M, Viola KL, and 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. in pressGoogle Scholar
  43. 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 Abeta 1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA 95:6448–6453PubMedCrossRefGoogle Scholar
  44. 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 79:595–605PubMedCrossRefGoogle Scholar
  45. Lambert MP, Lacor PN, Chang L, Viola KL, Velasco PT, Richardson DK, Gong Y, Krafft GA, Klein WL (2003) ADDL-generated monoclonal antibodies target epitopes specific to Aβ oligomers. 2003 Abstract Viewer/Itinerary Planner Washington, DC: Soci Neurosci Abstract No. 527.16Google Scholar
  46. Lambert MP, Velasco PT, Chang L, Viola KL, Fernandez S, Lacor PN, Khuon D, Gong Y, Bigio EH, Shaw P, De Felice FG, Krafft G, and Klein WL (2007) Monoclonal antibodies that target pathological assemblies of Abeta. J. Neurochem. 100:23–35PubMedCrossRefGoogle Scholar
  47. 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 440:352–357PubMedCrossRefGoogle Scholar
  48. Lesort M, Jope RS, Johnson GV (1999) Insulin transiently increases tau phosphorylation: involvement of glycogen synthase kinase-3beta and Fyn tyrosine kinase. J Neurochem 72:576–584PubMedCrossRefGoogle Scholar
  49. Levine H, III (1995) Soluble multimeric Alzheimer beta(1-40) pre-amyloid complexes in dilute solution. Neurobiol Aging 16:755–764PubMedCrossRefGoogle Scholar
  50. Levine H, III (2004) Alzheimer’s beta-peptide oligomer formation at physiologic concentrations. Anal Biochem 335:81–90PubMedCrossRefGoogle Scholar
  51. Masliah E, Miller A, Terry RD (1993) The synaptic organization of the neocortex in Alzheimer’s disease. Med Hypotheses 41:334–340PubMedCrossRefGoogle Scholar
  52. Matsuzaki M, Ellis-Davies GC, Nemoto T, Miyashita Y, Iino M, Kasai H (2001) Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons. Nature Neurosci 4:1086–1092PubMedCrossRefGoogle Scholar
  53. McLean CA, Cherny RA, Fraser FW, Fuller SJ, Smith MJ, Beyreuther K, Bush AI, Masters CL (1999) Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann Neurol 46:860–866PubMedCrossRefGoogle Scholar
  54. Mesulam MM (1999) Neuroplasticity failure in Alzheimer’s disease: bridging the gap between plaques and tangles. Neuron 24:521–529PubMedCrossRefGoogle Scholar
  55. Montalto MC, Agdeppa ED, Siclovan TM, Williams AC (2004) Composition and methods for non-invasive imaging of soluble beta-amyloid. New York/USA, Patent 10/747,715(US 2004/0223909 A1)Google Scholar
  56. 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 20:4050–4058PubMedGoogle Scholar
  57. Mukaetova-Ladinska EB, Garcia-Siera F, Hurt J, Gertz HJ, Xuereb JH, Hills R, Brayne C, Huppert FA, Paykel ES, McGee M, Jakes R, Honer WG, Harrington CR, Wischik CM (2000) Staging of cytoskeletal and beta-amyloid changes in human isocortex reveals biphasic synaptic protein response during progression of Alzheimer’s disease. Am J Pathol 157:623–636PubMedGoogle Scholar
  58. Nomura I, Kato N, Kita T, Takechi H (2005) Mechanismof impairment of long-term potentiation by amyloid beta is independent of NMDA receptors or voltage-dependent calcium channels in hippocampal CA1 pyramidal neurons. Neurosci Lett 391:1–6PubMedCrossRefGoogle Scholar
  59. Oda T, Pasinetti GM, Osterburg HH, Anderson C, Johnson SA, Finch CE (1994) Purification and characterization of brain clusterin. Biochem Biophys Res Commun 204:1131–1136PubMedCrossRefGoogle Scholar
  60. Oda T, Wals P, Osterburg HH, Johnson SA, Pasinetti GM, Morgan TE, Rozovsky I, Stine WB, Snyder SW, Holzman TF (1995) Clusterin (apoJ) alters the aggregation of amyloid beta-peptide (Aβ 1-42) and forms slowly sedimenting Aβ complexes that cause oxidative stress. Exp Neurol 136:22–31PubMedCrossRefGoogle Scholar
  61. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39:409–421PubMedCrossRefGoogle Scholar
  62. 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 281:1599–1604PubMedCrossRefGoogle Scholar
  63. Ohno M, Chang L, Tseng W, Oakley H, Citron M, Klein WL, Vassar R, Disterhoft JF (2005) Temporal memory deficits in Alzheimer’s mouse models: Rescue by genetic deletion of BACE1 with reduced amyloid-β oligomers. Eur J Neurosci 23:251–260CrossRefGoogle Scholar
  64. Palop JJ, Chin J, Bien-Ly N, Massaro C, Yeung BZ, Yu GQ, Mucke L (2005) Vulnerability of dentate granule cells to disruption of arc expression in human amyloid precursor protein transgenic mice. J Neurosci 25:9686–9693PubMedCrossRefGoogle Scholar
  65. Puzzo D, Vitolo O, Trinchese F, Jacob JP, Palmeri A, Arancio O (2005) Amyloid-beta peptide inhibits activation of the nitric oxide/cGMP/cAMP-responsive element-binding protein pathway during hippocampal synaptic plasticity. J Neurosci 25:6887–6897PubMedCrossRefGoogle Scholar
  66. Reixach N, Deechongkit S, Jiang X, Kelly JW, Buxbaum JN (2004) Tissue damage in the amyloidoses: Transthyretin monomers and nonnative oligomers are the major cytotoxic species in tissue culture. Proc Natl Acad Sci USA 101:2817–2822PubMedCrossRefGoogle Scholar
  67. Scheff SW, Price DA (2003) Synaptic pathology in Alzheimer’s disease: a review of ultrastructural studies. Neurobiol Aging 24:1029–1046PubMedCrossRefGoogle Scholar
  68. Serrano F, Klann E (2004) Reactive oxygen species and synaptic plasticity in the aging hippocampus. Ageing Res Rev 3:431–443PubMedCrossRefGoogle Scholar
  69. Sheng M, Lee SH (2001) AMPA receptor trafficking and the control of synaptic transmission. Cell 105:825–828PubMedCrossRefGoogle Scholar
  70. Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, Nairn AC, Salter MW, Lombroso PJ, Gouras GK, Greengard P (2005) Regulation of NMDA receptor trafficking by amyloid-beta. Nature Neurosci 8:1051–1058PubMedCrossRefGoogle Scholar
  71. Steward O, Worley P (2002) Local synthesis of proteins at synaptic sites on dendrites: role in synaptic plasticity and memory consolidation? Neurobiol Learn Mem 78:508–527PubMedCrossRefGoogle Scholar
  72. Takahashi RH, Almeida CG, Kearney PF, Yu F, Lin MT, Milner TA, Gouras GK (2004) Oligomerization of Alzheimer’s beta-amyloid within processes and synapses of cultured neurons and brain. J Neurosci 24:3592–3599PubMedCrossRefGoogle Scholar
  73. Tong L, Thornton PL, Balazs R, Cotman CW (2001) Beta-amyloid-(1–42) impairs activitydependent cAMP-response element-binding protein signaling in neurons at concentrations in which cell survival Is not compromised. J Biol Chem 276:17301–17306PubMedCrossRefGoogle Scholar
  74. Trommer BL, Shah C, Yun SH, Gamkrelidze G, Pasternak ES, Blaine SW, Manelli A, Sullivan P, Pasternak JF, LaDu MJ (2005) ApoE isoform-specific effects on LTP: blockade by oligomeric amyloid-beta1-42. Neurobiol Dis 18:75–82PubMedCrossRefGoogle Scholar
  75. Vitolo OV, Sant’Angelo A, Costanzo V, Battaglia F, Arancio O, Shelanski M (2002) Amyloid beta-peptide inhibition of the PKA/CREB pathway and long-term potentiation: reversibility by drugs that enhance cAMP signaling. Proc Natl Acad Sci USA 99:13217–13221PubMedCrossRefGoogle Scholar
  76. 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 416:535–539PubMedCrossRefGoogle Scholar
  77. Walsh DM, Townsend M, Podlisny MB, Shankar GM, Fadeeva JV, Agnaf OE, Hartley DM, Selkoe DJ (2005) Certain inhibitors of synthetic amyloid beta-peptide (Abeta) fibrillogenesis block oligomerization of natural Abeta and thereby rescue long-term potentiation. J Neurosci 25:2455–2462PubMedCrossRefGoogle Scholar
  78. 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 924:133–140PubMedCrossRefGoogle Scholar
  79. Wang Q, Walsh DM, Rowan MJ, Selkoe DJ, Anwyl R (2004a) Block of long-term potentiation by naturally secreted and synthetic amyloid beta-peptide in hippocampal slices is mediated via activation of the kinases c-Jun N-terminal kinase, cyclin-dependent kinase 5, and p38 mitogen-activated protein kinase as well as metabotropic glutamate receptor type 5. J Neurosci 24:3370–3378PubMedCrossRefGoogle Scholar
  80. Wang Z, Chang L, Klein WL, Thatcher GR, Venton DL (2004b) Per-6-substituted-per-6-deoxy beta-cyclodextrins inhibit the formation of beta-amyloid peptide derived soluble oligomers. J Med Chem 47:3329–3333PubMedCrossRefGoogle Scholar
  81. Westerman MA, Chang L, Frautschy S, Kotilinek L, Cole G, Klein W, Hsiao Ashe K (2002) Ibuprofen reverses memory loss in transgenic mice modeling Alzheimer’s disease. Soc Neurosci Abstract 28:690.4Google Scholar
  82. Witt A, Macdonald N, Kirkpatrick P (2004) Memantine hydrochloride. Nature Rev Drug Discov 3:109–110CrossRefGoogle Scholar
  83. Zhang C, Qiu HE, Krafft GA, Klein WL (1996) A beta peptide enhances focal adhesion kinase/Fyn association in a rat CNS nerve cell line. Neurosci Lett 211:187–190PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2007

Authors and Affiliations

  • William L. Klein
    • 1
  • Pascale N. Lacor
    • 1
  • Fernanda G. De Felice
    • 1
  • Sergio T. Ferreira
    • 1
  1. 1.Cognitive Neurology & Alzheimer’s Disease Center, Department of Neurobiology and PhysiologyNorthwestern University Institute for NeuroscienceEvanstonUSA

Personalised recommendations