About this Journal Submit a Manuscript Table of Contents
Journal of Biomedicine and Biotechnology
Volume 2011 (2011), Article ID 697036, 9 pages
http://dx.doi.org/10.1155/2011/697036
Review Article

A Window into the Heterogeneity of Human Cerebrospinal Fluid Aβ Peptides

1Proteomics Unit, IRCCS “Centro S. Giovanni di Dio-FBF”, 25125 Brescia, Italy
2NeuroBioGen Lab-Memory Clinic, IRCCS “Centro S. Giovanni di Dio-FBF”, 25125 Brescia, Italy
3Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden
4IRCCS San Camillo, Lido VE, 30126 Venice, Italy

Received 1 June 2011; Revised 27 June 2011; Accepted 30 June 2011

Academic Editor: Thomas Van Groen

Copyright © 2011 Roberta Ghidoni et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. C. L. Masters, G. Simms, N. A. Weinman, G. Multhaup, B. L. McDonald, and K. Beyreuther, “Amyloid plaque core protein in Alzheimer disease and Down syndrome,” Proceedings of the National Academy of Sciences of the United States of America, vol. 82, no. 12, pp. 4245–4249, 1985.
  2. J. Hardy and D. J. Selkoe, “The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics,” Science, vol. 297, no. 5580, pp. 353–356, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  3. C. A. Lemere and E. Masliah, “Can Alzheimer disease be prevented by amyloid-β immunotherapy?” Nature Reviews Neurology, vol. 6, no. 2, pp. 108–119, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  4. C. Haass, M. G. Schlossmacher, A. Y. Hung et al., “Amyloid β-peptide is produced by cultured cells during normal metabolism,” Nature, vol. 359, no. 6393, pp. 322–325, 1992. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  5. T. C. Saido, T. Iwatsubo, D. M. A. Mann, H. Shimada, Y. Ihara, and S. Kawashima, “Dominant and differential deposition of distinct β-amyloid peptide species, AβN3(pE), in senile plaques,” Neuron, vol. 14, no. 2, pp. 457–466, 1995. View at Scopus
  6. T. Iwatsubo, T. C. Saido, D. M. A. Mann, V. M. Y. Lee, and J. Q. Trojanowski, “Full-length amyloid-β(1-42(43)) and amino-terminally modified and truncated amyloid-β42(43) deposit in diffuse plaques,” American Journal of Pathology, vol. 149, no. 6, pp. 1823–1830, 1996. View at Scopus
  7. C. Russo, T. C. Saido, L. M. DeBusk, M. Tabaton, P. Gambetti, and J. K. Teller, “Heterogeneity of water-soluble amyloid β-peptide in Alzheimer's disease and Down's syndrome brains,” FEBS Letters, vol. 409, no. 3, pp. 411–416, 1997. View at Publisher · View at Google Scholar · View at Scopus
  8. C. Russo, G. Schettini, T. C. Saido et al., “Presenilin-1 mutations in Alzheimer's disease,” Nature, vol. 405, no. 6786, pp. 531–532, 2000. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  9. E. Portelius, N. Bogdanovic, M. K. Gustavsson et al., “Mass spectrometric characterization of brain amyloid beta isoform signatures in familial and sporadic Alzheimer's disease,” Acta Neuropathologica, vol. 120, no. 2, pp. 185–193, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  10. C. Russo, S. Salis, V. Dolcini, et al., “Amino-terminal modification and tyrosine phosphorylation of carboxy-terminal fragments of the amyloid precursor protein in Alzheimer's disease and Down's syndrome brain,” Neurobiology of Disease, vol. 8, no. 1, pp. 173–180, 2001.
  11. N. Sergeant, S. Bombois, A. Ghestem et al., “Truncated beta-amyloid peptide species in pre-clinical Alzheimer's disease as new targets for the vaccination approach,” Journal of Neurochemistry, vol. 85, no. 6, pp. 1581–1591, 2003. View at Publisher · View at Google Scholar · View at Scopus
  12. K. Liu, I. Solano, D. Mann et al., “Characterization of Abeta11-40/42 peptide deposition in Alzheimer's disease and young Down's syndrome brains: implication of N-terminally truncated Abeta species in the pathogenesis of Alzheimer's disease,” Acta neuropathologica, vol. 112, no. 2, pp. 163–174, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  13. S. S. Sisodia, “β-Amyloid precursor protein cleavage by a membrane-bound protease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 13, pp. 6075–6079, 1992. View at Publisher · View at Google Scholar · View at Scopus
  14. R. Vassar, B. D. Bennett, S. Babu-Khan et al., “β-Secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE,” Science, vol. 286, no. 5440, pp. 735–741, 1999. View at Publisher · View at Google Scholar · View at Scopus
  15. K. Liu, R. W. Doms, and V. M. Y. Lee, “Glu11 site cleavage and N-terminally truncated Aβ production upon BACE overexpression,” Biochemistry, vol. 41, no. 9, pp. 3128–3136, 2002. View at Publisher · View at Google Scholar · View at Scopus
  16. E. Portelius, E. Price, G. Brinkmalm et al., “A novel pathway for amyloid precursor protein processing,” Neurobiology of Aging, vol. 32, no. 6, pp. 1090–1098, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  17. F. Kametani, “ε-secretase: reduction of amyloid precursor protein ε-site cleavage in Alzheimer's disease,” Current Alzheimer Research, vol. 5, no. 2, pp. 165–171, 2008. View at Publisher · View at Google Scholar · View at Scopus
  18. E. Portelius, B. Zhang, M. K. Gustavsson et al., “Effects of γ-secretase inhibition on the amyloid β isoform pattern in a mouse model of Alzheimer's disease,” Neurodegenerative Diseases, vol. 6, no. 5-6, pp. 258–262, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  19. G. McKhann, D. Drachman, and M. Folstein, “Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease,” Neurology, vol. 34, no. 7, pp. 939–944, 1984.
  20. B. Dubois, H. H. Feldman, C. Jacova et al., “Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria,” Lancet Neurology, vol. 6, no. 8, pp. 734–746, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  21. B. Dubois, H. H. Feldman, C. Jacova et al., “Revising the definition of Alzheimer's disease: a new lexicon,” The Lancet Neurology, vol. 9, no. 11, pp. 1118–1127, 2010. View at Publisher · View at Google Scholar · View at Scopus
  22. G. M. McKhann, D. S. Knopman, H. Chertkow et al., “The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease,” Alzheimer's and Dementia, vol. 7, no. 3, pp. 263–269, 2011. View at Publisher · View at Google Scholar · View at PubMed
  23. M. S. Albert, S. T. DeKosky, D. Dickson et al., “The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease,” Alzheimer's and Dementia, vol. 7, no. 3, pp. 270–279, 2011. View at Publisher · View at Google Scholar · View at PubMed
  24. R. A. Sperling, P. S. Aisen, L. A. Beckett et al., “Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease,” Alzheimer's and Dementia, vol. 7, no. 3, pp. 280–292, 2011. View at Publisher · View at Google Scholar · View at PubMed
  25. K. Blennow, H. Hampel, M. Weiner, and H. Zetterberg, “Cerebrospinal fluid and plasma biomarkers in Alzheimer disease,” Nature Reviews Neurology, vol. 6, no. 3, pp. 131–144, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  26. N. Mattsson, H. Zetterberg, O. Hansson et al., “CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment,” Journal of the American Medical Association, vol. 302, no. 4, pp. 385–393, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  27. P. J. Visser, F. Verhey, D. L. Knol et al., “Prevalence and prognostic value of CSF markers of Alzheimer's disease pathology in patients with subjective cognitive impairment or mild cognitive impairment in the DESCRIPA study: a prospective cohort study,” The Lancet Neurology, vol. 8, no. 7, pp. 619–627, 2009. View at Publisher · View at Google Scholar · View at Scopus
  28. L. M. Shaw, H. Vanderstichele, M. Knapik-Czajka et al., “Cerebrospinal fluid biomarker signature in alzheimer's disease neuroimaging initiative subjects,” Annals of Neurology, vol. 65, no. 4, pp. 403–413, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  29. G. B. Frisoni, A. Prestia, O. Zanetti et al., “Markers of Alzheimer's disease in a population attending a memory clinic,” Alzheimer's and Dementia, vol. 5, no. 4, pp. 307–317, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  30. S. Galluzzi, C. Geroldi, R. Ghidoni et al., “Translational outpatient memory clinic working group. The new Alzheimer's criteria in a naturalistic series of patients with mild cognitive impairment,” Journal of Neurology, vol. 257, no. 12, pp. 2004–2014, 2010. View at Publisher · View at Google Scholar · View at PubMed
  31. M. Kanai, E. Matsubara, K. Isoe et al., “Longitudinal study of cerebrospinal fluid levels of tau, Aβ1-40, and Aβ1-42(43) in Alzheimer's disease: a study in Japan,” Annals of Neurology, vol. 44, no. 1, pp. 17–26, 1998. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  32. P. D. Mehta, T. Pirttilä, S. P. Mehta, E. A. Sersen, P. S. Aisen, and H. M. Wisniewski, “Plasma and cerebrospinal fluid levels of amyloid β proteins 1-40 and 1- 42 in Alzheimer disease,” Archives of Neurology, vol. 57, no. 1, pp. 100–105, 2000. View at Scopus
  33. R. Fukuyama, T. Mizuno, T. Mizuno et al., “Age-dependent change in the levels of Aβ40 and Aβ42 in cerebrospinal fluid from control subjects, and a decrease in the ratio of Aβ42 to Aβ40 level in cerebrospinal fluid from Alzheimer's disease patients,” European Neurology, vol. 43, no. 3, pp. 155–160, 2000. View at Scopus
  34. O. Hansson, H. Zetterberg, P. Buchhave et al., “Prediction of Alzheimer's disease using the CSF Aβ42/Aβ40 ratio in patients with mild cognitive impairment,” Dementia and Geriatric Cognitive Disorders, vol. 23, no. 5, pp. 316–320, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  35. A. M. Fagan, D. Head, A. R. Shah et al., “Decreased cerebrospinal fluid Aβ42 correlates with brain atrophy in cognitively normal elderly,” Annals of Neurology, vol. 65, no. 2, pp. 176–183, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  36. C. M. Roe, A. M. Fagan, M. M. Williams et al., “Improving CSF biomarker accuracy in predicting prevalent and incident Alzheimer disease,” Neurology, vol. 76, no. 6, pp. 501–510, 2011. View at Publisher · View at Google Scholar · View at PubMed
  37. S. Rolstad, A. I. Berg, M. Bjerke, et al., “Amyloid-β42 is associated with cognitive impairment in healthy elderly and subjective cognitive impairment,” Journal of Alzheimer’s Disease,. In press.
  38. A. Cedazo-Minguez and B. Winblad, “Biomarkers for Alzheimer's disease and other forms of dementia: clinical needs, limitations and future aspects,” Experimental Gerontology, vol. 45, no. 1, pp. 5–14, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  39. M. Bibl, B. Mollenhauer, S. Wolf et al., “Reduced CSF carboxyterminally truncated Aβ peptides in frontotemporal lobe degenerations,” Journal of Neural Transmission, vol. 114, no. 5, pp. 621–628, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  40. M. Bibl, B. Mollenhauer, H. Esselmann et al., “CSF diagnosis of Alzheimer's disease and dementia with Lewy bodies,” Journal of Neural Transmission, vol. 113, no. 11, pp. 1771–1778, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  41. N. Andreasen and H. Zetterberg, “Amyloid-related biomarkers for Alzheimer's disease,” Current Medicinal Chemistry, vol. 15, no. 8, pp. 766–771, 2008. View at Publisher · View at Google Scholar · View at Scopus
  42. E. Gowing, A. E. Roher, A. S. Woods et al., “Chemical characterization of Aβ 17-42 peptide, a component of diffuse amyloid deposits of Alzheimer disease,” Journal of Biological Chemistry, vol. 269, no. 15, pp. 10987–10990, 1994. View at Scopus
  43. J. Näslund, A. Schierhorn, U. Hellman et al., “Relative abundance of Alzheimer Aβ amyloid peptide variants in Alzheimer disease and normal aging,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 18, pp. 8378–8382, 1994. View at Scopus
  44. Y. Harigaya, T. C. Saido, C. B. Eckman, C. M. Prada, M. Shoji, and S. G. Younkin, “Amyloid β protein starting pyroglutamate at position 3 is a major component of the amyloid deposits in the Alzheimer's disease brain,” Biochemical and Biophysical Research Communications, vol. 276, no. 2, pp. 422–427, 2000. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  45. L. Miravalle, M. Calero, M. Takao, A. E. Roher, B. Ghetti, and R. Vidal, “Amino-terminally truncated Aβ peptide species are the main component of cotton wool plaques,” Biochemistry, vol. 44, no. 32, pp. 10810–10821, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  46. A. Piccini, C. Russo, A. Gliozzi et al., “β-amyloid is different in normal aging and in Alzheimer disease,” Journal of Biological Chemistry, vol. 280, no. 40, pp. 34186–34192, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  47. E. Portelius, A. Westman-Brinkmalm, H. Zetterberg, and K. Blennow, “Determination of β-amyloid peptide signatures in cerebrospinal fluid using immunoprecipitation-mass spectrometry,” Journal of Proteome Research, vol. 5, no. 4, pp. 1010–1016, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  48. E. Portelius, A. J. Tran, U. Andreasson et al., “Characterization of amyloid β peptides in cerebrospinal fluid by an automated immunoprecipitation procedure followed by mass spectrometry,” Journal of Proteome Research, vol. 6, no. 11, pp. 4433–4439, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  49. E. Portelius, U. Andreasson, J. M. Ringman et al., “Distinct cerebrospinal fluid amyloid peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer's disease,” Molecular Neurodegeneration, vol. 5, no. 1, article 2, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  50. A. S. Maddalena, A. Papassotiropoulos, C. Gonzalez-Agosti et al., “Cerebrospinal fluid profile of amyloid β peptides in patients with Alzheimer's disease determined by protein biochip technology,” Neurodegenerative Diseases, vol. 1, no. 4-5, pp. 231–235, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  51. V. Albertini, A. Bruno, A. Paterlini et al., “Optimization protocol for amyloid-β peptides detection in human cerebrospinal fluid using SELDI TOF MS,” Proteomics - Clinical Applications, vol. 4, no. 3, pp. 352–357, 2010. View at Publisher · View at Google Scholar · View at Scopus
  52. E. Portelius, H. Zetterberg, U. Andreasson et al., “An Alzheimer's disease-specific β-amyloid fragment signature in cerebrospinal fluid,” Neuroscience Letters, vol. 409, no. 3, pp. 215–219, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  53. C. Vigo-Pelfrey, D. Lee, P. Keim, I. Lieberburg, and D. B. Schenk, “Characterization of β-amyloid peptide from human cerebrospinal fluid,” Journal of Neurochemistry, vol. 61, no. 5, pp. 1965–1968, 1993. View at Publisher · View at Google Scholar · View at Scopus
  54. R. Ghidoni, V. Albertini, R. Squitti et al., “Novel T719P AβPP mutation unbalances the relative proportion of amyloid-β peptides,” Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 295–303, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  55. P. Lewczuk, H. Esselmann, M. Meyer et al., “The amyloid-β (Aβ) peptide pattern in cerebrospinal fluid in Alzheimer's disease: evidence of a novel carboxyterminally elongated Aβ peptide,” Rapid Communications in Mass Spectrometry, vol. 17, no. 12, pp. 1291–1296, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  56. H. Vanderstichele, G. De Meyer, N. Andreasen et al., “Amino-truncated β-amyloid42 peptides in cerebrospinal fluid and prediction of progression of mild cognitive impairment,” Clinical Chemistry, vol. 51, no. 9, pp. 1650–1660, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  57. J. Wiltfang, H. Esselmann, M. Bibl et al., “Highly conserved and disease-specific patterns of carboxyterminally truncated Aβ peptides 1-37/38/39 in addition to 1-40/42 in Alzheimer's disease and in patients with chronic neuroinflammation,” Journal of Neurochemistry, vol. 81, no. 3, pp. 481–496, 2002. View at Publisher · View at Google Scholar · View at Scopus
  58. P. Lewczuk, H. Esselmann, T. W. Groemer et al., “Amyloid β peptides in cerebrospinal fluid as profiled with surface enhanced laser desorption/ionization time-of-flight mass spectrometry: evidence of novel biomarkers in Alzheimer's disease,” Biological Psychiatry, vol. 55, no. 5, pp. 524–530, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  59. E. Portelius, R. A. Dean, M. K. Gustavsson, et al., “A novel abeta isoform pattern in CSF reflects gamma-secretase inhibition in Alzheimer disease,” Alzheimer’s Research & Theraphy, vol. 2, no. 7, pp. 1–7, 2010.
  60. D. M. Walsh and D. J. Selkoe, “Aβ oligomers—a decade of discovery,” Journal of Neurochemistry, vol. 101, no. 5, pp. 1172–1184, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  61. W. Xia, T. Yang, G. Shankar et al., “A specific enzyme-linked immunosorbent assay for measuring β-amyloid protein oligomers in human plasma and brain tissue of patients with Alzheimer Disease,” Archives of Neurology, vol. 66, no. 2, pp. 190–199, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  62. M. P. Lambert, A. K. Barlow, B. A. Chromy et al., “Diffusible, nonfibrillar ligands derived from Aβ1-42 are potent central nervous system neurotoxins,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 11, pp. 6448–6453, 1998. View at Scopus
  63. D. M. Hartley, D. M. Walsh, C. P. Ye et al., “Protofibrillar intermediates of amyloid β-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons,” Journal of Neuroscience, vol. 19, no. 20, pp. 8876–8884, 1999. View at Scopus
  64. R. Kayed, Y. Sokolov, B. Edmonds et al., “Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases,” Journal of Biological Chemistry, vol. 279, no. 45, pp. 46363–46366, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  65. L. Mucke, E. Masliah, G. Q. Yu et al., “High-level neuronal expression of Aβ(1-42) in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation,” Journal of Neuroscience, vol. 20, no. 11, pp. 4050–4058, 2000. View at Scopus
  66. S. Lesné, T. K. Ming, L. Kotilinek et al., “A specific amyloid-β protein assembly in the brain impairs memory,” Nature, vol. 440, no. 7082, pp. 352–357, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  67. D. M. Walsh, I. Klyubin, J. V. Fadeeva et al., “Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo,” Nature, vol. 416, no. 6880, pp. 535–539, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  68. I. Klyubin, D. M. Walsh, C. A. Lemere et al., “Amyloid β protein immunotherapy neutralizes Aβ oligomers that disrupt synaptic plasticity in vivo,” Nature Medicine, vol. 11, no. 5, pp. 556–561, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  69. G. M. Shankar, S. Li, T. H. Mehta et al., “Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory,” Nature Medicine, vol. 14, no. 8, pp. 837–842, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  70. M. N. Reed, J. J. Hofmeister, L. Jungbauer, et al., “Cognitive effects of cell-derived and synthetically derived Abeta oligomers,” Neurobiology of Aging, vol. 32, no. 10, pp. 1784–1794, 2011. View at Publisher · View at Google Scholar · View at PubMed
  71. S. Li, M. Jin, T. Koeglsperger, N. E. Shepardson, G. M. Shankar, and D. J. Selkoe, “Soluble a β oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors,” Journal of Neuroscience, vol. 31, no. 18, pp. 6627–6638, 2011. View at Publisher · View at Google Scholar · View at PubMed
  72. M. Pitschke, R. Prior, M. Haupt, and D. Riesner, “Detection of single amyloid β-protein aggregates in the cerebrospinal fluid of Alzheirner's patients by fluorescence correlation spectroscopy,” Nature Medicine, vol. 4, no. 7, pp. 832–834, 1998. View at Publisher · View at Google Scholar · View at Scopus
  73. D. G. Georganopoulou, L. Chang, J. M. Nam et al., “Nanoparticle-based detection in cerebral spinal fluid of a soluble pathogenic biomarker for Alzheimer's disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 7, pp. 2273–2276, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  74. A. N. Santos, S. Torkler, D. Nowak et al., “Detection of amyloid-β oligomers in human cerebrospinal fluid by flow cytometry and fluorescence resonance energy transfer,” Journal of Alzheimer's Disease, vol. 11, no. 1, pp. 117–125, 2007. View at Scopus
  75. I. Klyubin, V. Betts, A. T. Welzel et al., “Amyloid β protein dimer-containing human CSF disrupts synaptic plasticity: prevention by systemic passive immunization,” Journal of Neuroscience, vol. 28, no. 16, pp. 4231–4237, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  76. H. Englund, M. D. Gunnarsson, R. M. Brundin et al., “Oligomerization partially explains the lowering of Aβ42 in alzheimer's disease cerebrospinal fluid,” Neurodegenerative Diseases, vol. 6, no. 4, pp. 139–147, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  77. H. Fukumoto, T. Tokuda, T. Kasai, et al., “High-molecular-weight beta-amyloid oligomers are elevated in cerebrospinal fluid of Alzheimer patients,” The Journal the Federation of American Societies for Experimental Biology, vol. 24, no. 8, pp. 2716–2726, 2010.
  78. C. M. Gao, A. Y. Yam, E. Magdangal et al., “Aβ40 oligomers identified as a potential biomarker for the diagnosis of alzheimer's disease,” PLoS One, vol. 5, no. 12, Article ID e15725, 2010. View at Publisher · View at Google Scholar · View at PubMed
  79. R. Kayed, E. Head, J. L. Thompson et al., “Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis,” Science, vol. 300, no. 5618, pp. 486–489, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  80. B. O'Nuallain and R. Wetzel, “Conformational Abs recognizing a generic amyloid fibril epitope,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 3, pp. 1485–1490, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  81. M. P. Lambert, P. T. Velasco, L. Chang et al., “Monoclonal antibodies that target pathological assemblies of Aβ,” Journal of Neurochemistry, vol. 100, no. 1, pp. 23–35, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  82. G. Habicht, C. Haupt, R. P. Friedrich et al., “Directed selection of a conformational antibody domain that prevents mature amyloid fibril formation by stabilizing Aβ protofibrils,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 49, pp. 19232–19237, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  83. G. Meli, M. Visintin, I. Cannistraci, and A. Cattaneo, “Direct in vivo intracellular selection of conformation-sensitive antibody domains targeting Alzheimer's amyloid-β oligomers,” Journal of Molecular Biology, vol. 387, no. 3, pp. 584–606, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  84. L. F. Agnati, G. Leo, S. Genedani et al., “Common key-signals in learning and neurodegeneration: focus on excito-amino acids, β-amyloid peptides and α-synuclein,” Journal of Neural Transmission, vol. 116, no. 8, pp. 953–974, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  85. L. F. Agnati and K. Fuxe, “Volume transmission as a key feature of information handling in the central nervous system possible new interpretative value of the Turing's B-type machine,” Progress in Brain Research, vol. 125, pp. 3–19, 2000. View at Publisher · View at Google Scholar · View at Scopus
  86. A. Lakkaraju and E. Rodriguez-Boulan, “Itinerant exosomes: emerging roles in cell and tissue polarity,” Trends in Cell Biology, vol. 18, no. 5, pp. 199–209, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  87. E. Cocucci, G. Racchetti, and J. Meldolesi, “Shedding microvesicles: artefacts no more,” Trends in Cell Biology, vol. 19, no. 2, pp. 43–51, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  88. M. Simons and G. Raposo, “Exosomes—vesicular carriers for intercellular communication,” Current Opinion in Cell Biology, vol. 21, no. 4, pp. 575–581, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  89. A. Rustom, “Hen or egg? Some thoughts on tunneling nanotubes,” Annals of the New York Academy of Sciences, vol. 1178, pp. 129–136, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  90. L. F. Agnati, S. Genedani, G. Leo et al., “Aβ peptides as one of the crucial volume transmission signals in the trophic units and their interactions with homocysteine. Physiological implications and relevance for Alzheimer's disease,” Journal of Neural Transmission, vol. 114, no. 1, pp. 21–31, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  91. K. Vekrellis, Z. Ye, W. Q. Qiu et al., “Neurons regulate extracellular levels of amyloid β-protein via proteolysis by insulin-degrading enzyme,” Journal of Neuroscience, vol. 20, no. 5, pp. 1657–1665, 2000. View at Scopus
  92. C. Hock, S. Golombowski, F. Müller-Spahn et al., “Cerebrospinal fluid levels of amyloid precursor protein and amyloid β-peptide in Alzheimer's disease and major depression—inverse correlation with dementia severity,” European Neurology, vol. 39, no. 2, pp. 111–118, 1998. View at Publisher · View at Google Scholar · View at Scopus
  93. S. A. Funke, E. Birkmann, and D. Willbold, “Detection of amyloid-β aggregates in body fluids: a suitable method for early diagnosis of Alzheimer's disease?” Current Alzheimer Research, vol. 6, no. 3, pp. 285–289, 2009. View at Publisher · View at Google Scholar · View at Scopus
  94. T. Oe, B. L. Ackermann, K. Inoue et al., “Quantitative analysis of amyloid β peptides in cerebrospinal fluid of Alzheimer's disease patients by immunoaffinity purification and stable isotope dilution liquid chromatography/negative electrospray ionization tandem mass spectrometry,” Rapid Communications in Mass Spectrometry, vol. 20, no. 24, pp. 3723–3735, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  95. L. Rajendran, M. Honsho, T. R. Zahn et al., “Alzheimer's disease β-amyloid peptides are released in association with exosomes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 30, pp. 11172–11177, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  96. V. Vingtdeux, M. Hamdane, A. Loyens et al., “Alkalizing drugs induce accumulation of amyloid precursor protein by-products in luminal vesicles of multivesicular bodies,” Journal of Biological Chemistry, vol. 282, no. 25, pp. 18197–18205, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  97. R. A. Sharples, L. J. Vella, R. M. Nisbet et al., “Inhibition of γ-secretase causes increased secretion of amyloid precursor protein C-terminal fragments in association with exosomes,” The Journal of the Federation of American Societies for Experimental Biology, vol. 22, no. 5, pp. 1469–1478, 2008. View at Publisher · View at Google Scholar · View at PubMed
  98. R. Ghidoni, L. Benussi, and G. Binetti, “Exosomes: the Trojan horses of neurodegeneration,” Medical Hypotheses, vol. 70, no. 6, pp. 1226–1227, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  99. R. Ghidoni, A. Paterlini, V. Albertini et al., “Cystatin C is released in association with exosomes: a new tool of neuronal communication which is unbalanced in Alzheimer's disease,” Neurobiology of Aging, vol. 32, no. 8, pp. 1435–1442, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  100. L. F. Agnati, D. Guidolin, F. Baluka et al., “A new hypothesis of pathogenesis based on the divorce between mitochondria and their host cells: possible relevance for alzheimer's disease,” Current Alzheimer Research, vol. 7, no. 4, pp. 307–322, 2010. View at Publisher · View at Google Scholar · View at Scopus
  101. E. Y. Chi, S. L. Frey, and K. Y. C. Lee, “Ganglioside GM1-mediated amyloid-beta fibrillogenesis and membrane disruption,” Biochemistry, vol. 46, no. 7, pp. 1913–1924, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  102. K. Yuyama, N. Yamamoto, and K. Yanagisawa, “Accelerated release of exosome-associated GM1 ganglioside (GM1) by endocytic pathway abnormality: another putative pathway for GM1-induced amyloid fibril formation,” Journal of Neurochemistry, vol. 105, no. 1, pp. 217–224, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  103. R. N. Re and J. L. Cook, “Senescence, apoptosis, and stem cell biology: the rationale for an expanded view of intracrine action,” American Journal of Physiology, Heart and Circulatory Physiology, vol. 297, no. 3, pp. H893–H901, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  104. A. Y. Lai and J. McLaurin, “Mechanisms of amyloid-beta peptide uptake by neurons: the role of lipid rafts and lipid raft-associated proteins,” International Journal of Alzheimer's Disease, vol. 2011, Article ID 548380, 11 pages, 2011. View at Publisher · View at Google Scholar · View at PubMed
  105. H. A. Pearson and C. Peers, “Physiological roles for amyloid β peptides,” Journal of Physiology, vol. 575, no. 1, pp. 5–10, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  106. A. Garcia-Osta and C. M. Alberini, “Amyloid beta mediates memory formation,” Neurobiology of Learning and Memory, vol. 16, no. 4, pp. 267–272, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  107. S. J. Soscia, J. E. Kirby, K. J. Washicosky et al., “The Alzheimer's disease-associated amyloid β-protein is an antimicrobial peptide,” PLoS One, vol. 5, no. 3, Article ID e9505, pp. 1–10, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  108. E. Tanzi, “I fatti e le induzione nell’odierna istologia del sistema nervoso,” Rivista sperimentale di freniatria e medicina legale delle alienazioni mentali, vol. 19, pp. 419–472, 1893.
  109. J. S. Taylor and R. M. Gaze, “The effects of the fibre environment on the paths taken by regenerating optic nerve fibres in Xenopus,” Journal of Embryology and Experimental Morphology, vol. 89, pp. 383–401, 1985. View at Scopus
  110. L. F. Agnati, M. Zoli, G. Biagini, and K. Fuxe, “Neuronal plasticity and ageing processes in the frame of the 'Red Queen Theory',” Acta Physiologica Scandinavica, vol. 145, no. 4, pp. 301–309, 1992. View at Scopus
  111. K. Yamada and T. Nabeshima, “Brain-derived neurotrophic factor/TrkB signaling in memory processes,” Journal Pharmacological Sciences, vol. 91, no. 4, pp. 267–270, 2003. View at Scopus
  112. K. Schindowski, K. Belarbi, and L. Buée, “Neurotrophic factors in Alzheimer's disease: role of axonal transport,” Genes, Brain and Behavior, vol. 7, no. 1, pp. 43–56, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  113. E. E. Tuppo and H. R. Arias, “The role of inflammation in Alzheimer's disease,” International Journal of Biochemistry and Cell Biology, vol. 37, no. 2, pp. 289–305, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus