Table of Contents Author Guidelines Submit a Manuscript
Neural Plasticity
Volume 2012, Article ID 247150, 8 pages
http://dx.doi.org/10.1155/2012/247150
Review Article

Synapses and Dendritic Spines as Pathogenic Targets in Alzheimer’s Disease

Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA

Received 21 August 2011; Revised 31 October 2011; Accepted 31 October 2011

Academic Editor: Tara Spires-Jones

Copyright © 2012 Wendou Yu and Bingwei Lu. 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. S. A. Eichler and J. C. Meier, “E-I balance and human diseases—from molecules to networking,” Frontiers in Molecular Neuroscience, vol. 1, article 2, 2008. View at Google Scholar
  2. D. Keith and A. El-Husseini, “Excitation control: balancing PSD-95 function at the synapse,” Frontiers in Molecular Neuroscience, vol. 1, article 4, 2008. View at Google Scholar
  3. G. G. Turrigiano and S. B. Nelson, “Homeostatic plasticity in the developing nervous system,” Nature Reviews Neuroscience, vol. 5, no. 2, pp. 97–107, 2004. View at Google Scholar · View at Scopus
  4. W. Yu and A. L. D. Blas, “Gephyrin expression and clustering affects the size of glutamatergic synaptic contacts,” Journal of Neurochemistry, vol. 104, no. 3, pp. 830–845, 2008. View at Publisher · View at Google Scholar · View at Scopus
  5. F. Stief, W. Zuschratter, K. Hartmann, D. Schmitz, and A. Draguhn, “Enhanced synaptic excitation-inhibition ratio in hippocampal interneurons of rats with temporal lobe epilepsy,” European Journal of Neuroscience, vol. 25, no. 2, pp. 519–528, 2007. View at Publisher · View at Google Scholar · View at Scopus
  6. D. A. Lewis and P. Levitt, “Schizophrenia as a disorder of neurodevelopment,” Annual Review of Neuroscience, vol. 25, pp. 409–432, 2002. View at Publisher · View at Google Scholar · View at Scopus
  7. J. A. Tsiouris and W. T. Brown, “Neuropsychiatric symptoms of fragile X syndrome: pathophysiology and pharmacotherapy,” CNS Drugs, vol. 18, no. 11, pp. 687–703, 2004. View at Publisher · View at Google Scholar · View at Scopus
  8. T. Deonna and E. Roulet, “Autistic spectrum disorder: evaluating a possible contributing or causal role of epilepsy,” Epilepsia, vol. 47, supplement 2, pp. 79–82, 2006. View at Publisher · View at Google Scholar · View at Scopus
  9. E. R. Kandel and J. H. Schwartz, “Molecular biology of learning: modulation of transmitter release,” Science, vol. 218, no. 4571, pp. 433–443, 1982. View at Google Scholar · View at Scopus
  10. R. C. Malenka and M. F. Bear, “LTP and LTD: an embarrassment of riches,” Neuron, vol. 44, no. 1, pp. 5–21, 2004. View at Publisher · View at Google Scholar · View at Scopus
  11. T. V. P. Bliss and T. Lomo, “Long lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path,” The Journal of Physiology, vol. 232, no. 2, pp. 331–356, 1973. View at Google Scholar · View at Scopus
  12. G. S. Lynch, T. Dunwiddie, and V. Gribkoff, “Heterosynaptic depression: a postsynaptic correlate of long term potentiation,” Nature, vol. 266, no. 5604, pp. 737–739, 1977. View at Google Scholar · View at Scopus
  13. C. Lüscher, H. Xia, E. C. Beattie et al., “Role of AMPA receptor cycling in synaptic transmission and plasticity,” Neuron, vol. 24, no. 3, pp. 649–658, 1999. View at Google Scholar · View at Scopus
  14. H. Y. Man, J. W. Lin, W. H. Ju et al., “Regulation of AMPA receptor-mediated synaptic transmission by clathrin-dependent receptor internalization,” Neuron, vol. 25, no. 3, pp. 649–662, 2000. View at Google Scholar · View at Scopus
  15. E. M. Snyder, B. D. Philpot, K. M. Huber, X. Dong, J. R. Fallon, and M. F. Bear, “Internalization of ionotropic glutamate receptors in response to mGluR activation,” Nature Neuroscience, vol. 4, no. 11, pp. 1079–1085, 2001. View at Publisher · View at Google Scholar · View at Scopus
  16. M. Y. Xiao, Q. Zhou, and R. A. Nicoll, “Metabotropic glutamate receptor activation causes a rapid redistribution of AMPA receptors,” Neuropharmacology, vol. 41, no. 6, pp. 664–671, 2001. View at Publisher · View at Google Scholar · View at Scopus
  17. S. H. Lee, L. Liu, Y. T. Wang, and M. Sheng, “Clathrin adaptor AP2 and NSF interact with overlapping sites of GluR2 and play distinct roles in AMPA receptor trafficking and hippocampal LTD,” Neuron, vol. 36, no. 4, pp. 661–674, 2002. View at Publisher · View at Google Scholar · View at Scopus
  18. U. V. Nägerl, N. Eberhorn, S. B. Cambridge, and T. Bonhoeffer, “Bidirectional activity-dependent morphological plasticity in hippocampal neurons,” Neuron, vol. 44, no. 5, pp. 759–767, 2004. View at Publisher · View at Google Scholar · View at Scopus
  19. Q. Zhou, K. J. Homma, and M. M. Poo, “Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses,” Neuron, vol. 44, no. 5, pp. 749–757, 2004. View at Publisher · View at Google Scholar · View at Scopus
  20. J. N. Bourne and K. M. Harris, “Balancing structure and function at hippocampal dendritic spines,” Annual Review of Neuroscience, vol. 31, pp. 47–67, 2008. View at Publisher · View at Google Scholar · View at Scopus
  21. J. C. Fiala, J. Spacek, and K. M. Harris, “Dendritic spine pathology: cause or consequence of neurological disorders?” Brain Research Reviews, vol. 39, no. 1, pp. 29–54, 2002. View at Publisher · View at Google Scholar · View at Scopus
  22. W. J. Schulz-Schaeffer, “The synaptic pathology of α-synuclein aggregation in dementia with Lewy bodies, Parkinson's disease and Parkinson's disease dementia,” Acta Neuropathologica, vol. 120, no. 2, pp. 131–143, 2010. View at Publisher · View at Google Scholar · View at Scopus
  23. M. van Spronsen and C. C. Hoogenraad, “Synapse pathology in psychiatric and neurologic disease,” Current Neurology and Neuroscience Reports, vol. 10, no. 3, pp. 207–214, 2010. View at Publisher · View at Google Scholar · View at Scopus
  24. P. Penzes, M. E. Cahill, K. A. Jones, J.-E. Vanleeuwen, and K. M. Woolfrey, “Dendritic spine pathology in neuropsychiatric disorders,” Nature Neuroscience, vol. 14, no. 3, pp. 285–293, 2011. View at Publisher · View at Google Scholar
  25. G. K. Gouras, D. Tampellini, R. H. Takahashi, and E. Capetillo-Zarate, “Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer's disease,” Acta Neuropathologica, vol. 119, no. 5, pp. 523–541, 2010. View at Publisher · View at Google Scholar · View at Scopus
  26. D. J. Selkoe and D. Schenk, “Alzheimer's disease: molecular understanding predicts amyloid-based therapeutics,” Annual Review of Pharmacology and Toxicology, vol. 43, pp. 545–584, 2003. View at Publisher · View at Google Scholar · View at Scopus
  27. D. M. Holtzman, J. C. Morris, and A. M. Goate, “Alzheimer's disease: the challenge of the second century,” Science Translational Medicine, vol. 3, no. 77, article 77sr1, 2011. View at Publisher · View at Google Scholar
  28. D. J. Selkoe, “Alzheimer's disease is a synaptic failure,” Science, vol. 298, no. 5594, pp. 789–791, 2002. View at Publisher · View at Google Scholar · View at Scopus
  29. S. T. DeKosky and S. W. Scheff, “Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity,” Annals of Neurology, vol. 27, no. 5, pp. 457–464, 1990. View at Google Scholar · View at Scopus
  30. D. J. Selkoe, “Amyloid β protein precursor and the pathogenesis of Alzheimer's disease,” Cell, vol. 58, no. 4, pp. 611–612, 1989. View at Google Scholar · View at Scopus
  31. J. Tsai, J. Grutzendler, K. Duff, and W. B. Gan, “Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches,” Nature Neuroscience, vol. 7, no. 11, pp. 1181–1183, 2004. View at Publisher · View at Google Scholar · View at Scopus
  32. T. L. Spires, M. Meyer-Luehmann, E. A. Stern et al., “Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy,” Journal of Neuroscience, vol. 25, no. 31, pp. 7278–7287, 2005. View at Publisher · View at Google Scholar · View at Scopus
  33. T. L. Spires-Jones, M. Meyer-Luehmann, J. D. Osetek et al., “Impaired spine stability underlies plaque-related spine loss in an Alzheimer's disease mouse model,” The American Journal of Pathology, vol. 171, no. 4, pp. 1304–1311, 2007. View at Publisher · View at Google Scholar · View at Scopus
  34. D. J. Selkoe, “Soluble oligomers of the amyloid β-protein impair synaptic plasticity and behavior,” Behavioural Brain Research, vol. 192, no. 1, pp. 106–113, 2008. View at Publisher · View at Google Scholar · View at Scopus
  35. S. S. Sisodia and D. L. Price, “Role of the β-amyloid protein in Alzheimer's disease,” The FASEB Journal, vol. 9, no. 5, pp. 366–370, 1995. View at Google Scholar · View at Scopus
  36. F. Kamenetz, T. Tomita, H. Hsieh et al., “APP processing and synaptic function,” Neuron, vol. 37, no. 6, pp. 925–937, 2003. View at Publisher · View at Google Scholar · View at Scopus
  37. 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 Scopus
  38. B. A. Yankner, L. R. Dawes, S. Fisher, L. Villa-Komaroff, M. L. Oster-Granite, and R. L. Neve, “Neurotixicity of a fragment of the amyloid precursor associated with Alzheimer's disease,” Science, vol. 245, no. 4916, pp. 417–420, 1989. View at Google Scholar · View at Scopus
  39. 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 Scopus
  40. M. Jin, N. Shepardson, T. Yang, G. Chen, D. Walsh, and D. J. Selkoe, “Soluble amyloid β-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 14, pp. 5819–5824, 2011. View at Publisher · View at Google Scholar
  41. 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 Google Scholar · View at Scopus
  42. L. M. Billings, S. Oddo, K. N. Green, J. L. McGaugh, and F. M. LaFerla, “Intraneuronal Aβ causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice,” Neuron, vol. 45, no. 5, pp. 675–688, 2005. View at Publisher · View at Google Scholar · View at Scopus
  43. N. Arispe, E. Rojas, and H. B. Pollard, “Alzheimer disease amyloid β protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 2, pp. 567–571, 1993. View at Publisher · View at Google Scholar · View at Scopus
  44. H. A. Lashuel, D. Hartley, B. M. Petre, T. Walz, and P. T. Lansbury, “Neurodegenerative disease: amyloid pores from pathogenic mutations,” Nature, vol. 418, no. 6895, article 291, p. 291, 2002. View at Google Scholar · View at Scopus
  45. H. Hsieh, J. Boehm, C. Sato et al., “AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss,” Neuron, vol. 52, no. 5, pp. 831–843, 2006. View at Publisher · View at Google Scholar · View at Scopus
  46. G. M. Shankar, B. L. Bloodgood, M. Townsend, D. M. Walsh, D. J. Selkoe, and B. L. Sabatini, “Natural oligomers of the Alzheimer amyloid-β protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway,” Journal of Neuroscience, vol. 27, no. 11, pp. 2866–2875, 2007. View at Publisher · View at Google Scholar · View at Scopus
  47. S. Li, S. Hong, N. E. Shepardson, D. M. Walsh, G. M. Shankar, and D. Selkoe, “Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake,” Neuron, vol. 62, no. 6, pp. 788–801, 2009. View at Publisher · View at Google Scholar · View at Scopus
  48. J. J. Palop, J. Chin, E. D. Roberson et al., “Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease,” Neuron, vol. 55, no. 5, pp. 697–711, 2007. View at Publisher · View at Google Scholar · View at Scopus
  49. M. T. Lin and M. F. Beal, “Alzheimer's APP mangles mitochondria,” Nature Medicine, vol. 12, no. 11, pp. 1241–1243, 2006. View at Publisher · View at Google Scholar · View at Scopus
  50. R. A. Nixon and A. M. Cataldo, “Lysosomal system pathways: genes to neurodegeneration in Alzheimer's disease,” Journal of Alzheimer's Disease, vol. 9, supplement 3, pp. 277–289, 2006. View at Google Scholar · View at Scopus
  51. C. G. Almeida, D. Tampellini, R. H. Takahashi et al., “Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses,” Neurobiology of Disease, vol. 20, no. 2, pp. 187–198, 2005. View at Publisher · View at Google Scholar · View at Scopus
  52. E. Kim and M. Sheng, “PDZ domain proteins of synapses,” Nature Reviews Neuroscience, vol. 5, no. 10, pp. 771–781, 2004. View at Publisher · View at Google Scholar · View at Scopus
  53. K. H. Gylys, J. A. Fein, F. Yang, D. J. Wiley, C. A. Miller, and G. M. Cole, “Snaptic changes in alzheimer's disease: increased amyloid-β and gliosis in surviving terminals is accompanied by decreased PSD-95 fluorescence,” The American Journal of Pathology, vol. 165, no. 5, pp. 1809–1817, 2004. View at Google Scholar · View at Scopus
  54. Y. Zhang, H. Guo, H. Kwan, J. W. Wang, J. Kosek, and B. Lu, “PAR-1 kinase phosphorylates Dlg and regulates its postsynaptic targeting at the Drosophila neuromuscular junction,” Neuron, vol. 53, no. 2, pp. 201–215, 2007. View at Publisher · View at Google Scholar · View at Scopus
  55. J. W. Wang, Y. Imai, and B. Lu, “Activation of PAR-1 kinase and stimulation of tau phosphorylation by diverse signals require the tumor suppressor protein LKB1,” The Journal of Neuroscience, vol. 27, no. 3, pp. 574–581, 2007. View at Publisher · View at Google Scholar · View at Scopus
  56. H. Zempel, E. Thies, E. Mandelkow, and E. M. Mandelkow, “Aβ oligomers cause localized Ca2+ elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines,” The Journal of Neuroscience, vol. 30, no. 36, pp. 11938–11950, 2010. View at Publisher · View at Google Scholar · View at Scopus
  57. V. M. Y. Lee, M. Goedert, and J. Q. Trojanowski, “Neurodegenerative tauopathies,” Annual Review of Neuroscience, vol. 24, pp. 1121–1159, 2001. View at Publisher · View at Google Scholar · View at Scopus
  58. T. L. Spires-Jones, W. H. Stoothoff, A. de Calignon, P. B. Jones, and B. T. Hyman, “Tau pathophysiology in neurodegeneration: a tangled issue,” Trends in Neurosciences, vol. 32, no. 3, pp. 150–159, 2009. View at Publisher · View at Google Scholar · View at Scopus
  59. P. Davies, “A very incomplete comprehensive theory of Alzheimer's disease,” Annals of the New York Academy of Sciences, vol. 924, pp. 8–16, 2000. View at Google Scholar · View at Scopus
  60. V. M. Y. Lee, “Biomedicine: tauists and ßaptists united—well almost!,” Science, vol. 293, no. 5534, pp. 1446–1447, 2001. View at Publisher · View at Google Scholar · View at Scopus
  61. J. Lewis, D. W. Dickson, W. L. Lin et al., “Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP,” Science, vol. 293, no. 5534, pp. 1487–1491, 2001. View at Publisher · View at Google Scholar · View at Scopus
  62. J. Götz, F. Chen, J. van Dorpe, and R. M. Nitsch, “Formation of neurofibrillary tangles in P301L tau transgenic mice induced by Aβ42 fibrils,” Science, vol. 293, no. 5534, pp. 1491–1495, 2001. View at Publisher · View at Google Scholar · View at Scopus
  63. S. Oddo, A. Caccamo, J. D. Shepherd et al., “Triple-transgenic model of Alzheimer's Disease with plaques and tangles: intracellular Aβ and synaptic dysfunction,” Neuron, vol. 39, no. 3, pp. 409–421, 2003. View at Publisher · View at Google Scholar · View at Scopus
  64. S. Oddo, L. Billings, J. P. Kesslak, D. H. Cribbs, and F. M. LaFerla, “Aβ immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome,” Neuron, vol. 43, no. 3, pp. 321–332, 2004. View at Publisher · View at Google Scholar · View at Scopus
  65. M. Rapoport, H. N. Dawson, L. I. Binder, M. P. Vitek, and A. Ferreira, “Tau is essential to β-amyloid-induced neurotoxicity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 9, pp. 6364–6369, 2002. View at Publisher · View at Google Scholar · View at Scopus
  66. G. N. Patrick, L. Zukerberg, M. Nikolic, S. De La Monte, P. Dikkes, and L. H. Tsai, “Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration,” Nature, vol. 402, no. 6762, pp. 615–622, 1999. View at Publisher · View at Google Scholar · View at Scopus
  67. J. C. Cruz, D. Kim, L. Y. Moy et al., “p25/cyclin-dependent kinase 5 induces production and intraneuronal accumulation of amyloid β in vivo,” The Journal of Neuroscience, vol. 26, no. 41, pp. 10536–10541, 2006. View at Publisher · View at Google Scholar · View at Scopus
  68. C. Zhang, H. E. Qiu, G. A. Krafft, and W. L. Klein, “Aβ peptide enhances focal adhesion kinase/Fyn association in a rat CNS nerve cell line,” Neuroscience Letters, vol. 211, no. 3, pp. 187–190, 1996. View at Publisher · View at Google Scholar · View at Scopus
  69. J. Chin, J. J. Palop, G. Q. Yu, N. Kojima, E. Masliah, and L. Mucke, “Fyn kinase modulates synaptotoxicity, but not aberrant sprouting, in human amyloid precursor protein transgenic mice,” The Journal of Neuroscience, vol. 24, no. 19, pp. 4692–4697, 2004. View at Publisher · View at Google Scholar · View at Scopus
  70. L. Baum, L. Hansen, E. Masliah, and T. Saitoh, “Glycogen synthase kinase 3 alteration in Alzheimer disease is related to neurofibrillary tangle formation,” Molecular and Chemical Neuropathology, vol. 29, no. 2-3, pp. 253–261, 1996. View at Google Scholar · View at Scopus
  71. G. Drewes, A. Ebneth, U. Preuss, E. M. Mandelkow, and E. Mandelkow, “MARK, a novel family of protein kinases that phosphorylate microtubule- associated proteins and trigger microtubule disruption,” Cell, vol. 89, no. 2, pp. 297–308, 1997. View at Google Scholar · View at Scopus
  72. I. Nishimura, Y. Yang, and B. Lu, “PAR-1 kinase plays an initiator role in a temporally ordered phosphorylation process that confers tau toxicity in Drosophila,” Cell, vol. 116, no. 5, pp. 671–682, 2004. View at Publisher · View at Google Scholar · View at Scopus
  73. J. Y. Chin, R. B. Knowles, A. Schneider, G. Drewes, E. M. Mandelkow, and B. T. Hyman, “Microtubule-affinity regulating kinase (MARK) is tightly associated with neurofibrillary tangles in Alzheimer brain: a fluorescence resonance energy transfer study,” Journal of Neuropathology and Experimental Neurology, vol. 59, no. 11, pp. 966–971, 2000. View at Google Scholar · View at Scopus
  74. E. D. Roberson, K. Scearce-Levie, J. J. Palop et al., “Reducing endogenous tau ameliorates amyloid β-induced deficits in an Alzheimer's disease mouse model,” Science, vol. 316, no. 5825, pp. 750–754, 2007. View at Publisher · View at Google Scholar · View at Scopus
  75. L. M. Ittner, Y. D. Ke, F. Delerue et al., “Dendritic function of tau mediates amyloid-β toxicity in alzheimer's disease mouse models,” Cell, vol. 142, no. 3, pp. 387–397, 2010. View at Publisher · View at Google Scholar · View at Scopus
  76. B. R. Hoover, M. N. Reed, J. Su et al., “Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration,” Neuron, vol. 68, no. 6, pp. 1067–1081, 2010. View at Publisher · View at Google Scholar · View at Scopus
  77. G. Lee, S. Todd Newman, D. L. Gard, H. Band, and G. Panchamoorthy, “Tau interacts with src-family non-receptor tyrosine kinases,” Journal of Cell Science, vol. 111, no. 21, pp. 3167–3177, 1998. View at Google Scholar · View at Scopus
  78. S. K. Shirazi and J. G. Wood, “The protein tyrosine kinase, fyn, in Alzheimer's disease pathology,” NeuroReport, vol. 4, no. 4, pp. 435–437, 1993. View at Google Scholar · View at Scopus
  79. L. M. Ittner and J. Götz, “Amyloid-β and tau—a toxic pas de deux in Alzheimer's disease,” Nature Reviews Neuroscience, vol. 12, no. 2, pp. 65–72, 2011. View at Publisher · View at Google Scholar · View at Scopus
  80. M. M. Bolton and C. Eroglu, “Look who is weaving the neural web: glial control of synapse formation,” Current Opinion in Neurobiology, vol. 19, no. 5, pp. 491–497, 2009. View at Publisher · View at Google Scholar · View at Scopus
  81. K. S. Christopherson, E. M. Ullian, C. C. A. Stokes et al., “Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis,” Cell, vol. 120, no. 3, pp. 421–433, 2005. View at Publisher · View at Google Scholar · View at Scopus
  82. Ç. Eroglu, N. J. Allen, M. W. Susman et al., “Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis,” Cell, vol. 139, no. 2, pp. 380–392, 2009. View at Publisher · View at Google Scholar · View at Scopus
  83. B. A. Barres, “The mystery and magic of glia: a perspective on their roles in health and disease,” Neuron, vol. 60, no. 3, pp. 430–440, 2008. View at Publisher · View at Google Scholar · View at Scopus
  84. B. Stevens, N. J. Allen, L. E. Vazquez et al., “The classical complement cascade mediates CNS synapse elimination,” Cell, vol. 131, no. 6, pp. 1164–1178, 2007. View at Publisher · View at Google Scholar · View at Scopus
  85. M. A. Carmona, K. K. Murai, L. Wang, A. J. Roberts, and E. B. Pasqualea, “Glial ephrin-A3 regulates hippocampal dendritic spine morphology and glutamate transport,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 30, pp. 12524–12529, 2009. View at Publisher · View at Google Scholar · View at Scopus
  86. M. Cissé, B. Halabisky, J. Harris et al., “Reversing EphB2 depletion rescues cognitive functions in Alzheimer model,” Nature, vol. 469, no. 7328, pp. 47–52, 2011. View at Publisher · View at Google Scholar
  87. T. Wyss-Coray, “Inflammation in Alzheimer disease: driving force, bystander or beneficial response?” Nature Medicine, vol. 12, no. 9, pp. 1005–1015, 2006. View at Publisher · View at Google Scholar · View at Scopus
  88. P. Agostinho, R. A. Cunha, and C. Oliveira, “Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer's disease,” Current Pharmaceutical Design, vol. 16, no. 25, pp. 2766–2778, 2010. View at Google Scholar · View at Scopus
  89. A. Cagnin, D. J. Brooks, A. M. Kennedy et al., “In-vivo measurement of activated microglia in dementia,” The Lancet, vol. 358, no. 9280, pp. 461–467, 2001. View at Publisher · View at Google Scholar · View at Scopus
  90. Y. Yoshiyama, M. Higuchi, B. Zhang et al., “Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model,” Neuron, vol. 53, no. 3, pp. 337–351, 2007. View at Publisher · View at Google Scholar · View at Scopus
  91. T. Tomiyama, S. Matsuyama, H. Iso et al., “A mouse model of amyloid β oligomers: their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo,” The Journal of Neuroscience, vol. 30, no. 14, pp. 4845–4856, 2010. View at Publisher · View at Google Scholar · View at Scopus
  92. M. B. Graeber and W. J. Streit, “Microglia: biology and pathology,” Acta Neuropathologica, vol. 119, no. 1, pp. 89–105, 2010. View at Publisher · View at Google Scholar · View at Scopus
  93. M. Matos, E. Augusto, C. R. Oliveira, and P. Agostinho, “Amyloid-beta peptide decreases glutamate uptake in cultured astrocytes: involvement of oxidative stress and mitogen-activated protein kinase cascades,” Neuroscience, vol. 156, no. 4, pp. 898–910, 2008. View at Publisher · View at Google Scholar · View at Scopus
  94. L. Arnaud, N. K. Robakis, and M. E. Figueiredo-Pereira, “It may take inflammation, phosphorylation and ubiquitination to “tangle” in Alzheimer's disease,” Neurodegenerative Diseases, vol. 3, no. 6, pp. 313–319, 2007. View at Publisher · View at Google Scholar · View at Scopus
  95. T. D. Helton, T. Otsuka, M. C. Lee, Y. Mu, and M. D. Ehlers, “Pruning and loss of excitatory synapses by the parkin ubiquitin ligase,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 49, pp. 19492–19497, 2008. View at Publisher · View at Google Scholar · View at Scopus
  96. W. Yu, Y. Sun, S. Guo, and B. Lu, “The PINK1/Parkin pathway regulates mitochondrial dynamics and function in mammalian hippocampal and dopaminergic neurons,” Human Molecular Genetics, vol. 20, no. 16, pp. 3227–3240, 2011. View at Publisher · View at Google Scholar
  97. L. Skipper, K. Wilkes, M. Toft et al., “Linkage disequilibrium and association of MAPT H1 in Parkinson disease,” American Journal of Human Genetics, vol. 75, no. 4, pp. 669–677, 2004. View at Publisher · View at Google Scholar · View at Scopus