Pore-Forming Neurotoxin-Like Mechanism for Aβ Oligomer-Induced Synaptic Failure

  • Luis G. Aguayo
  • Jorge Parodi
  • Fernando J. Sepúlveda
  • Carlos Opazo


Cortical and hippocampal synapse densities are reduced in Alzheimer’s disease (AD), and this strongly correlates with memory dysfunction. It is now believed that these changes in neuronal networking occur at the onset of AD and may lead to the neuronal loss displayed in later stages of the disease, which is characterized by severe cognitive and behavioral impairments. Mounting evidence indicates that amyloid-β (Aβ) oligomers are responsible for synaptic disconnections and neuronal death. One of the main consequences of Aβ oligomers interaction with neurons is an increase in intracellular Ca2+ concentration that could, when large enough, cause a marked alteration in ionic homeostasis. It has also been postulated that Ca2+ influx occurs when Aβ oligomers induce the opening of Ca2+ channels or the disruption of the plasma membrane. We recently found that the effects of Aβ oligomers on synaptic transmission are similar to pore-forming toxins, such as α-latrotoxin, a neurotoxin from the black widow spider. Here, we discuss evidence supporting a neurotoxin-like mechanism for the effects induced by Aβ oligomers on neuronal membranes, which could explain the alterations in the functionality of synapses in the central nervous system in AD that leads to major neurodegeneration with time of exposure to Aβ oligomers.


Synaptic Transmission Neuronal Membrane Synaptic Dysfunction Synaptic Failure Black Widow Spider 
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.


amyloid-β peptide


Alzheimer's disease




amyloid-β protein precursor




long-term potentiation





This work was supported by FONDECYT Grant No 1060368, Ring of Research PBCT ACT-04 (L.G.A. and C.O). We would like to thank Lauren Aguayo for her revision of the manuscript.


  1. 1.
    Masters CL, Simms G, Weinman NA (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA 82:4245–4249PubMedCrossRefGoogle Scholar
  2. 2.
    Lesne S, Koh MT, Kotilinek L (2006) A specific amyloid-β protein assembly in the brain impairs memory. Nature 440:352–357PubMedCrossRefGoogle Scholar
  3. 3.
    Lambert MP, Barlow AK, Chromy BA (1998) Diffusible, nonfibrillar ligands derived from Aβ1–42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA 95:6448–6453PubMedCrossRefGoogle Scholar
  4. 4.
    McLean CA, Cherny RA, Fraser FW (1999) Soluble pool of Aβ amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann Neurol 46:860–866PubMedCrossRefGoogle Scholar
  5. 5.
    Walsh DM, Townsend M, Podlisny MB (2005) Certain inhibitors of synthetic amyloid β-peptide (Aβ) fibrillogenesis block oligomerization of natural Aβ and thereby rescue long-term potentiation. J Neurosci 25:2455–2462PubMedCrossRefGoogle Scholar
  6. 6.
    Grace EA, Rabiner CA, Busciglio J (2002) Characterization of neuronal dystrophy induced by fibrillar Aβ: implications for Alzheimer’s disease. Neuroscience 114:265–273PubMedCrossRefGoogle Scholar
  7. 7.
    Meyer-Luehmann M, Spires-Jones TL, Prada C (2008) Rapid appearance and local toxicity of Aβ plaques in a mouse model of Alzheimer’s disease. Nature 451:720–724PubMedCrossRefGoogle Scholar
  8. 8.
    Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791PubMedCrossRefGoogle Scholar
  9. 9.
    Kelly BL, Vassar R, Ferreira A (2005) Aβ-induced dynamin 1 depletion in hippocampal neurons. A potential mechanism for early cognitive decline in Alzheimer disease. J Biol Chem 280:31746–31753PubMedCrossRefGoogle Scholar
  10. 10.
    Snyder EM, Nong Y, Almeida CG (2005) Regulation of NMDA receptor trafficking by Aβ. Nat Neurosci 8:1051–1058PubMedCrossRefGoogle Scholar
  11. 11.
    Hsia AY, Masliah E, McConlogue L (1999) Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models. Proc Natl Acad Sci USA 96:3228–3233PubMedCrossRefGoogle Scholar
  12. 12.
    Terry RD, Masliah E, Salmon DP (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580PubMedCrossRefGoogle Scholar
  13. 13.
    Yao PJ (2004) Synaptic frailty and clathrin-mediated synaptic vesicle trafficking in Alzheimer’s disease. Trends Neurosci 27:24–29PubMedCrossRefGoogle Scholar
  14. 14.
    Mattson MP (2004) Pathways towards and away from Alzheimer’s disease. Nature 430:631–639PubMedCrossRefGoogle Scholar
  15. 15.
    Harkany T, Abraham I, Timmerman W (2000) Aβ neurotoxicity is mediated by a glutamate-triggered excitotoxic cascade in rat nucleus basalis. Eur J Neurosci 12:2735–2745PubMedCrossRefGoogle Scholar
  16. 16.
    Scragg JL, Fearon IM, Boyle JP (2005) Alzheimer’s amyloid peptides mediate hypoxic up-regulation of L-type Ca2+ channels. FASEB J 19:150–152PubMedGoogle Scholar
  17. 17.
    Kagan BL, Hirakura Y, Azimov R (2002) The channel hypothesis of Alzheimer’s disease: current status. Peptides 23:1311–1315PubMedCrossRefGoogle Scholar
  18. 18.
    Durell SR, Guy HR, Arispe N (1994) Theoretical models of the ion channel structure of Aβ-protein. Biophys J 67:2137–2145PubMedCrossRefGoogle Scholar
  19. 19.
    Arispe N, Rojas E, Pollard HB (1993) Alzheimer disease Aβ-protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum. Proc Natl Acad Sci USA 90:567–571PubMedCrossRefGoogle Scholar
  20. 20.
    Kawahara M, Kuroda Y, Arispe N (2000) Alzheimer’s Aβ, human islet amylin, and prion protein fragment evoke intracellular free calcium elevations by a common mechanism in a hypothalamic GnRH neuronal cell line. J Biol Chem 275:14077–14083PubMedCrossRefGoogle Scholar
  21. 21.
    Kawahara M, Arispe N, Kuroda Y (1997) Alzheimer’s disease Aβ-protein forms Zn2+-sensitive, cation-selective channels across excised membrane patches from hypothalamic neurons. Biophys J 73:67–75PubMedCrossRefGoogle Scholar
  22. 22.
    Bush AI, Pettingell WH, Multhaup G (1994) Rapid induction of Alzheimer Aβ amyloid formation by zinc. Science 265:1464–1467PubMedCrossRefGoogle Scholar
  23. 23.
    Kourie JI, Henry CL, Farrelly P (2001) Diversity of Aβ protein fragment [1–40]-formed channels. Cell Mol Neurobiol 21:255–284PubMedCrossRefGoogle Scholar
  24. 24.
    Kayed R, Sokolov Y, Edmonds B (2004) Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases. J Biol Chem 279:46363–46366.PubMedCrossRefGoogle Scholar
  25. 25.
    Bourin M, Ripoll N, Dailly E (2003) Nicotinic receptors and Alzheimer’s disease. Curr Med Res Opin 19:169–177PubMedCrossRefGoogle Scholar
  26. 26.
    Maccioni RB, Muñoz JP, Barbeito L (2001) The molecular bases of Alzheimer’s disease and other neurodegenerative disorders. Arch Med Res 32:367–381PubMedCrossRefGoogle Scholar
  27. 27.
    Van Renterghem C, Iborra C, Martin-Moutot N (2000) α-latrotoxin forms calcium-permeable membrane pores via interactions with latrophilin or neurexin. Eur J Neurosci 12:3953–3962PubMedCrossRefGoogle Scholar
  28. 28.
    Tsang CW, Elrick DB, Charlton MP (2000) α-Latroxin releases calcium in frog motor nerve terminals. J Neurosci 20:8685–8692.PubMedGoogle Scholar
  29. 29.
    Orlova EV, Rahman M, Gowen B (2000) Structure of α-latrotoxin oligomers reveals that divalent cation-dependent tetramers form membrane pores. Nat Struct Biol 7:48–53PubMedCrossRefGoogle Scholar
  30. 30.
    Liu J, Misler S (1998) α-Latrotoxin alters spontaneous and depolarization-evoked quantal release from rat adrenal chromaffin cells: evidence for multiple modes of action. J Neurosci 18:6113–6125PubMedGoogle Scholar
  31. 31.
    Tzeng MC, Cohen RS, Siekevitz P (1978) Release of neurotransmitters and depletion of synaptic vesicles in cerebral cortex slices by α-latrotoxin from black widow spider venom. Proc Natl Acad Sci USA 75:4016–4020PubMedCrossRefGoogle Scholar
  32. 32.
    Simakova O, Arispe NJ (2006) Early and late cytotoxic effects of external application of the Alzheimer’s Aβ result from the initial formation and function of Aβ ion channels. Biochemistry 45:5907–5915PubMedCrossRefGoogle Scholar
  33. 33.
    Parodi J, Sepúlveda FJ, Opazo C et al (2008) Alzheimer amyloid-β causes a potent membrane perforation in brain neurons. New mechanism for the development and discovery of anti AD drugs. Manuscript in preparationGoogle Scholar
  34. 34.
    Lal R, Lin H, Quist A (2007) Aβion channel: 3D structure and relevance to amyloid channel paradigm. Biochim Biophys Acta 1768:1966–1975PubMedCrossRefGoogle Scholar
  35. 35.
    Jang H, Zheng J, Nussinov R (2007) Models of Aβ ion channels in the membrane suggest that channel formation in the bilayer is a dynamic process. Biophys J 93:1938–1949PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Luis G. Aguayo
    • 1
  • Jorge Parodi
    • 1
  • Fernando J. Sepúlveda
    • 1
  • Carlos Opazo
    • 1
  1. 1.Department of PhysiologyUniversity of ConcepciónConcepción Chile

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