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Dendritic Spine Loss and Synaptic Alterations in Alzheimer’s Disease

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Abstract

Dendritic spines are tiny protrusions along dendrites, which constitute major postsynaptic sites for excitatory synaptic transmission. These spines are highly motile and can undergo remodeling even in the adult nervous system. Spine remodeling and the formation of new synapses are activity-dependent processes that provide a basis for memory formation. A loss or alteration of these structures has been described in patients with neurodegenerative disorders such as Alzheimer’s disease (AD), and in mouse models for these disorders. Such alteration is thought to be responsible for cognitive deficits long before or even in the absence of neuronal loss, but the underlying mechanisms are poorly understood. This review will describe recent findings and discoveries on the loss or alteration of dendritic spines induced by the amyloid β (Aβ) peptide in the context of AD.

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References

  1. Glickstein M (2001) Ramón y Cajal, Santiago. Encyclopedia of life sciences. Wiley, Chichester. Available at http://www.els.net

  2. Mazzarello P (2001) Golgi, Camillo. Encyclopedia of life sciences. Wiley, Chichester. Available at http://www.els.net

  3. Nimchinsky EA, Sabatini BL, Svoboda K (2002) Structure and function of dendritic spines. Annu Rev Physiol 64:313–353

    PubMed  CAS  Google Scholar 

  4. Denk W, Strickler JH, Webb WW (1990) Two-photon laser scanning fluorescence microscopy. Science 248:73–76

    PubMed  CAS  Google Scholar 

  5. Svoboda K, Yasuda R (2006) Principles of two-photon excitation microscopy and its applications to neuroscience. Neuron 50:823–839

    PubMed  CAS  Google Scholar 

  6. Trachtenberg JT, Chen BE, Knott GW, Feng G, Sanes JR, Welker E, Svoboda K (2002) Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex. Nature 420:788–794

    PubMed  CAS  Google Scholar 

  7. Grutzendler J, Kasthuri N, Gan WB (2002) Long-term dendritic spine stability in the adult cortex. Nature 420:812–816

    PubMed  CAS  Google Scholar 

  8. Mizrahi A, Crowley JC, Shtoyerman E, Katz LC (2004) High-resolution in vivo imaging of hippocampal dendrites and spines. J Neurosci 24:3147–3151

    PubMed  CAS  Google Scholar 

  9. Majewska AK, Newton JR, Sur M (2006) Remodeling of synaptic structure in sensory cortical areas in vivo. J Neurosci 26:3021–3029

    PubMed  CAS  Google Scholar 

  10. Alvarez VA, Sabatini BL (2007) Anatomical and physiological plasticity of dendritic spines. Annu Rev Neurosci 30:79–97

    PubMed  CAS  Google Scholar 

  11. Holtmaat AJ, Trachtenberg JT, Wilbrecht L, Shepherd GM, Zhang X, Knott GW, Svoboda K (2005) Transient and persistent dendritic spines in the neocortex in vivo. Neuron 45:279–291

    PubMed  CAS  Google Scholar 

  12. Holtmaat A, Wilbrecht L, Knott GW, Welker E, Svoboda K (2006) Experience-dependent and cell-type-specific spine growth in the neocortex. Nature 441:979–983

    PubMed  CAS  Google Scholar 

  13. Knott GW, Holtmaat A, Wilbrecht L, Welker E, Svoboda K (2006) Spine growth precedes synapse formation in the adult neocortex in vivo. Nat Neurosci 9:1117–1124

    PubMed  CAS  Google Scholar 

  14. Harris KM, Stevens JK (1989) Dendritic spines of CA 1 pyramidal cells in the rat hippocampus: serial electron microscopy with reference to their biophysical characteristics. J Neurosci 9:2982–2997

    PubMed  CAS  Google Scholar 

  15. Takumi Y, Ramirez-Leon V, Laake P, Rinvik E, Ottersen OP (1999) Different modes of expression of AMPA and NMDA receptors in hippocampal synapses. Nat Neurosci 2:618–624

    PubMed  CAS  Google Scholar 

  16. Zuo Y, Yang G, Kwon E, Gan WB (2005) Long-term sensory deprivation prevents dendritic spine loss in primary somatosensory cortex. Nature 436:261–265

    PubMed  CAS  Google Scholar 

  17. Zuo Y, Lin A, Chang P, Gan WB (2005) Development of long-term dendritic spine stability in diverse regions of cerebral cortex. Neuron 46:181–189

    PubMed  CAS  Google Scholar 

  18. Sekino Y, Kojima N, Shirao T (2007) Role of actin cytoskeleton in dendritic spine morphogenesis. Neurochem Int 51:92–104

    PubMed  CAS  Google Scholar 

  19. Matus A (2005) Growth of dendritic spines: a continuing story. Curr Opin Neurobiol 15:67–72

    PubMed  CAS  Google Scholar 

  20. Schubert V, Dotti CG (2007) Transmitting on actin: synaptic control of dendritic architecture. J Cell Sci 120:205–212

    PubMed  CAS  Google Scholar 

  21. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356

    PubMed  CAS  Google Scholar 

  22. Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 8:101–112

    PubMed  CAS  Google Scholar 

  23. Walsh DM, Selkoe DJ (2007) A beta oligomers—a decade of discovery. J Neurochem 101:1172–1184

    PubMed  CAS  Google Scholar 

  24. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580

    PubMed  CAS  Google Scholar 

  25. Scheff SW, Price DA (2006) Alzheimer’s disease-related alterations in synaptic density: neocortex and hippocampus. J Alzheimer’s Dis 9:101–115

    Google Scholar 

  26. Masliah E, Crews L, Hansen L (2006) Synaptic remodeling during aging and in Alzheimer’s disease. J Alzheimer’s Dis 9:91–99

    CAS  Google Scholar 

  27. Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791

    PubMed  CAS  Google Scholar 

  28. Scheff SW, Price DA, Schmitt FA, Mufson EJ (2006) Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging 27:1372–1384

    PubMed  CAS  Google Scholar 

  29. Scheff SW, Price DA, Schmitt FA, DeKosky ST, Mufson EJ (2007) Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology 68:1501–1508

    PubMed  CAS  Google Scholar 

  30. Honer WG (2003) Pathology of presynaptic proteins in Alzheimer’s disease: more than simple loss of terminals. Neurobiol Aging 24:1047–1062

    PubMed  CAS  Google Scholar 

  31. Reddy PH, Mani G, Park BS, Jacques J, Murdoch G, Whetsell W Jr, Kaye J, Manczak M (2005) Differential loss of synaptic proteins in Alzheimer’s disease: implications for synaptic dysfunction. J Alzheimer’s Dis 7:103–17, discussion 173–80

    CAS  Google Scholar 

  32. Ingelsson M, Fukumoto H, Newell KL, Growdon JH, Hedley-Whyte ET, Frosch MP, Albert MS, Hyman BT, Irizarry MC (2004) Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology 62:925–931

    PubMed  CAS  Google Scholar 

  33. 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 103:5161–5166

    PubMed  CAS  Google Scholar 

  34. Wu CC, Chawla F, Games D, Rydel RE, Freedman S, Schenk D, Young WG, Morrison JH, Bloom FE (2004) Selective vulnerability of dentate granule cells prior to amyloid deposition in PDAPP mice: digital morphometric analyses. Proc Natl Acad Sci USA 101:7141–7146

    PubMed  CAS  Google Scholar 

  35. Lanz TA, Carter DB, Merchant KM (2003) Dendritic spine loss in the hippocampus of young PDAPP and Tg2576 mice and its prevention by the ApoE2 genotype. Neurobiol Dis 13:246–253

    PubMed  CAS  Google Scholar 

  36. Spires-Jones TL, Meyer-Luehmann M, Osetek JD, Jones PB, Stern EA, Bacskai BJ, Hyman BT (2007) Impaired spine stability underlies plaque-related spine loss in an Alzheimer’s disease mouse model. Am J Pathol 171:1304–1311

    PubMed  CAS  Google Scholar 

  37. Grutzendler J, Helmin K, Tsai J, Gan WB (2007) Various dendritic abnormalities are associated with fibrillar amyloid deposits in Alzheimer’s disease. Ann N Y Acad Sci 1097:30–39

    PubMed  Google Scholar 

  38. Dong H, Martin MV, Chambers S, Csernansky JG (2007) Spatial relationship between synapse loss and beta-amyloid deposition in Tg2576 mice. J Comp Neurol 500:311–321

    PubMed  CAS  Google Scholar 

  39. Spires TL, Meyer-Luehmann M, Stern EA, McLean PJ, Skoch J, Nguyen PT, Bacskai BJ, Hyman BT (2005) Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy. J Neurosci 25:7278–7287

    PubMed  CAS  Google Scholar 

  40. Tsai J, Grutzendler J, Duff K, Gan WB (2004) Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Nat Neurosci 7:1181–1183

    PubMed  CAS  Google Scholar 

  41. Alpar A, Ueberham U, Bruckner MK, Seeger G, Arendt T, Gartner U (2006) Different dendrite and dendritic spine alterations in basal and apical arbors in mutant human amyloid precursor protein transgenic mice. Brain Res 1099:189–198

    PubMed  CAS  Google Scholar 

  42. Rutten BP, Van der Kolk NM, Schafer S, van Zandvoort MA, Bayer TA, Steinbusch HW, Schmitz C (2005) Age-related loss of synaptophysin immunoreactive presynaptic boutons within the hippocampus of APP751SL, PS1M146L, and APP751SL/PS1M146L transgenic mice. Am J Pathol 167:161–173

    PubMed  CAS  Google Scholar 

  43. Moolman DL, Vitolo OV, Vonsattel JP, Shelanski ML (2004) Dendrite and dendritic spine alterations in Alzheimer models. J Neurocytol 33:377–387

    PubMed  CAS  Google Scholar 

  44. 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 20:4050–4058

    PubMed  CAS  Google Scholar 

  45. Hauptmann S, Scherping I, Drose S, Brandt U, Schulz KL, Jendrach M, Leuner K, Eckert A, Muller WE (2008) Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice. Neurobiol Aging (in press)

  46. Li Z, Okamoto K, Hayashi Y, Sheng M (2004) The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 119:873–887

    PubMed  CAS  Google Scholar 

  47. Palop JJ, Chin J, Mucke L (2006) A network dysfunction perspective on neurodegenerative diseases. Nature 443:768–773

    PubMed  CAS  Google Scholar 

  48. McGowan E, Eriksen J, Hutton M (2006) A decade of modeling Alzheimer’s disease in transgenic mice. Trends Genet 22:281–289

    PubMed  CAS  Google Scholar 

  49. Hartley DM, Walsh DM, Ye CP, Diehl T, Vasquez S, Vassilev PM, Teplow DB, Selkoe DJ (1999) Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J Neurosci 19:8876–8884

    PubMed  CAS  Google Scholar 

  50. Chen QS, Kagan BL, Hirakura Y, Xie CW (2000) Impairment of hippocampal long-term potentiation by Alzheimer amyloid beta-peptides. J Neurosci Res 60:65–72

    PubMed  CAS  Google Scholar 

  51. 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 416:535–539

    PubMed  CAS  Google Scholar 

  52. 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 924:133–140

    PubMed  CAS  Google Scholar 

  53. 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 19:2839–2846

    PubMed  Google Scholar 

  54. Knobloch M, Farinelli M, Konietzko U, Nitsch RM, Mansuy IM (2007) Abeta oligomer-mediated long-term potentiation impairment involves protein phosphatase 1-dependent mechanisms. J Neurosci 27:7648–7653

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  56. 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 440:352–357

    PubMed  CAS  Google Scholar 

  57. Demuro A, Mina E, Kayed R, Milton SC, Parker I, Glabe CG (2005) Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. J Biol Chem 280:17294–17300

    PubMed  CAS  Google Scholar 

  58. Klein WL (2006) Synaptic targeting by Abeta oligomers (ADDLS) as a basis for memory loss in early Alzheimer’s disease. Alzheimer’s and Dementia 2:43–55

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  60. 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. Nat Neurosci 8:1051–1058

    PubMed  CAS  Google Scholar 

  61. Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL (2007) Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci 27:2866–2875

    PubMed  CAS  Google Scholar 

  62. Calabrese B, Shaked GM, Tabarean IV, Braga J, Koo EH, Halpain S (2007) Rapid, concurrent alterations in pre- and postsynaptic structure induced by naturally-secreted amyloid-beta protein. Mol Cell Neurosci 35:183–193

    PubMed  CAS  Google Scholar 

  63. Dewachter I, Filipkowski RK, Priller C, Ris L, Neyton J, Croes S, Terwel D, Gysemans M, Devijver H, Borghgraef P, Godaux E, Kaczmarek L, Herms J, Van Leuven F (2007) Deregulation of NMDA-receptor function and down-stream signaling in APP[V717I] transgenic mice. Neurobiol Aging (in press)

  64. Hsieh H, Boehm J, Sato C, Iwatsubo T, Tomita T, Sisodia S, Malinow R (2006) AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron 52:831–843

    PubMed  CAS  Google Scholar 

  65. Almeida CG, Tampellini D, Takahashi RH, Greengard P, Lin MT, Snyder EM, Gouras GK (2005) Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses. Neurobiol Dis 20:187–198

    PubMed  CAS  Google Scholar 

  66. Roselli F, Tirard M, Lu J, Hutzler P, Lamberti P, Livrea P, Morabito M, Almeida OF (2005) Soluble beta-amyloid1–40 induces NMDA-dependent degradation of postsynaptic density-95 at glutamatergic synapses. J Neurosci 25:11061–11070

    PubMed  CAS  Google Scholar 

  67. Chang EH, Savage MJ, Flood DG, Thomas JM, Levy RB, Mahadomrongkul V, Shirao T, Aoki C, Huerta PT (2006) AMPA receptor downscaling at the onset of Alzheimer’s disease pathology in double knockin mice. Proc Natl Acad Sci USA 103:3410–3415

    PubMed  CAS  Google Scholar 

  68. Bastrikova N, Gardner GA, Reece JM, Jeromin A, Dudek SM (2008) Synapse elimination accompanies functional plasticity in hippocampal neurons. Proc Natl Acad Sci USA 105:3123–3127

    PubMed  CAS  Google Scholar 

  69. Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Bien-Ly N, Yoo J, Ho KO, Yu GQ, Kreitzer A, Finkbeiner S, Noebels JL, Mucke L (2007) Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease. Neuron 55:697–711

    PubMed  CAS  Google Scholar 

  70. Mansuy IM, Shenolikar S (2006) Protein serine/threonine phosphatases in neuronal plasticity and disorders of learning and memory. Trends Neurosci 29:679–686

    PubMed  CAS  Google Scholar 

  71. Tian Q, Wang J (2002) Role of serine/threonine protein phosphatase in Alzheimer’s disease. NeuroSignals 11:262–269

    PubMed  CAS  Google Scholar 

  72. Liu F, Grundke-Iqbal I, Iqbal K, Oda Y, Tomizawa K, Gong CX (2005) Truncation and activation of calcineurin A by calpain I in Alzheimer disease brain. J Biol Chem 280:37755–37762

    PubMed  CAS  Google Scholar 

  73. Norris CM, Kadish I, Blalock EM, Chen KC, Thibault V, Porter NM, Landfield PW, Kraner SD (2005) Calcineurin triggers reactive/inflammatory processes in astrocytes and is upregulated in aging and Alzheimer’s models. J Neurosci 25:4649–4658

    PubMed  CAS  Google Scholar 

  74. Chen QS, Wei WZ, Shimahara T, Xie CW (2002) Alzheimer amyloid beta-peptide inhibits the late phase of long-term potentiation through calcineurin-dependent mechanisms in the hippocampal dentate gyrus. Neurobiol Learn Mem 77:354–371

    PubMed  CAS  Google Scholar 

  75. Kaytor MD, Orr HT (2002) The GSK3 beta signaling cascade and neurodegenerative disease. Curr Opin Neurobiol 12:275–278

    PubMed  CAS  Google Scholar 

  76. Rockenstein E, Torrance M, Adame A, Mante M, Bar-on P, Rose JB, Crews L, Masliah E (2007) Neuroprotective effects of regulators of the glycogen synthase kinase-3beta signaling pathway in a transgenic model of Alzheimer’s disease are associated with reduced amyloid precursor protein phosphorylation. J Neurosci 27:1981–1991

    PubMed  CAS  Google Scholar 

  77. Peineau S, Taghibiglou C, Bradley C, Wong TP, Liu L, Lu J, Lo E, Wu D, Saule E, Bouschet T, Matthews P, Isaac JT, Bortolotto ZA, Wang YT, Collingridge GL (2007) LTP inhibits LTD in the hippocampus via regulation of GSK3beta. Neuron 53:703–717

    PubMed  CAS  Google Scholar 

  78. Zhu LQ, Wang SH, Liu D, Yin YY, Tian Q, Wang XC, Wang Q, Chen JG, Wang JZ (2007) Activation of glycogen synthase kinase-3 inhibits long-term potentiation with synapse-associated impairments. J Neurosci 27:12211–12220

    PubMed  CAS  Google Scholar 

  79. Mazanetz MP, Fischer PM (2007) Untangling tau hyperphosphorylation in drug design for neurodegenerative diseases. Nat Rev Drug Discov 6:464–479

    PubMed  CAS  Google Scholar 

  80. Cruz JC, Kim D, Moy LY, Dobbin MM, Sun X, Bronson RT, Tsai LH (2006) p25/cyclin-dependent kinase 5 induces production and intraneuronal accumulation of amyloid beta in vivo. J Neurosci 26:10536–10541

    PubMed  CAS  Google Scholar 

  81. Samuels BA, Hsueh YP, Shu T, Liang H, Tseng HC, Hong CJ, Su SC, Volker J, Neve RL, Yue DT, Tsai LH (2007) Cdk5 promotes synaptogenesis by regulating the subcellular distribution of the MAGUK family member CASK. Neuron 56:823–837

    PubMed  CAS  Google Scholar 

  82. Fischer A, Sananbenesi F, Pang PT, Lu B, Tsai LH (2005) Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory. Neuron 48:825–838

    PubMed  CAS  Google Scholar 

  83. Fu WY, Chen Y, Sahin M, Zhao XS, Shi L, Bikoff JB, Lai KO, Yung WH, Fu AK, Greenberg ME, Ip NY (2007) Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism. Nat Neurosci 10:67–76

    PubMed  CAS  Google Scholar 

  84. Hawasli AH, Benavides DR, Nguyen C, Kansy JW, Hayashi K, Chambon P, Greengard P, Powell CM, Cooper DC, Bibb JA (2007) Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation. Nat Neurosci 10:880–886

    PubMed  CAS  Google Scholar 

  85. Zhao L, Ma QL, Calon F, Harris-White ME, Yang F, Lim GP, Morihara T, Ubeda OJ, Ambegaokar S, Hansen JE, Weisbart RH, Teter B, Frautschy SA, Cole GM (2006) Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease. Nat Neurosci 9:234–242

    PubMed  CAS  Google Scholar 

  86. Hayashi ML, Choi SY, Rao BS, Jung HY, Lee HK, Zhang D, Chattarji S, Kirkwood A, Tonegawa S (2004) Altered cortical synaptic morphology and impaired memory consolidation in forebrain- specific dominant-negative PAK transgenic mice. Neuron 42:773–787

    PubMed  CAS  Google Scholar 

  87. Zhao D, Watson JB, Xie CW (2004) Amyloid beta prevents activation of calcium/calmodulin-dependent protein kinase II and AMPA receptor phosphorylation during hippocampal long-term potentiation. J Neurophysiol 92:2853–2858

    PubMed  CAS  Google Scholar 

  88. Townsend M, Mehta T, Selkoe DJ (2007) Soluble abeta inhibits specific signal transduction cascades common to the insulin receptor pathway. J Biol Chem 282:33305–33312

    PubMed  CAS  Google Scholar 

  89. Mayford M (2007) Protein kinase signaling in synaptic plasticity and memory. Curr Opin Neurobiol 17:313–317

    PubMed  CAS  Google Scholar 

  90. Yamamoto-Sasaki M, Ozawa H, Saito T, Rosler M, Riederer P (1999) Impaired phosphorylation of cyclic AMP response element binding protein in the hippocampus of dementia of the Alzheimer type. Brain Res 824:300–303

    PubMed  CAS  Google Scholar 

  91. Gong B, Cao Z, Zheng P, Vitolo OV, Liu S, Staniszewski A, Moolman D, Zhang H, Shelanski M, Arancio O (2006) Ubiquitin hydrolase Uch-L1 rescues beta-amyloid-induced decreases in synaptic function and contextual memory. Cell 126:775–788

    PubMed  CAS  Google Scholar 

  92. Tong L, Thornton PL, Balazs R, Cotman CW (2001) Beta-amyloid-(1–42) impairs activity-dependent cAMP-response element-binding protein signaling in neurons at concentrations in which cell survival Is not compromised. J Biol Chem 276:17301–17306

    PubMed  CAS  Google Scholar 

  93. 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 99:13217–13221

    PubMed  CAS  Google Scholar 

  94. 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 25:6887–6897

    PubMed  CAS  Google Scholar 

  95. Reddy PH, McWeeney S (2006) Mapping cellular transcriptosomes in autopsied Alzheimer’s disease subjects and relevant animal models. Neurobiol Aging 27:1060–1077

    PubMed  CAS  Google Scholar 

  96. Dickey CA, Gordon MN, Mason JE, Wilson NJ, Diamond DM, Guzowski JF, Morgan D (2004) Amyloid suppresses induction of genes critical for memory consolidation in APP + PS1 transgenic mice. J Neurochem 88:434–442

    PubMed  CAS  Google Scholar 

  97. Dickey CA, Loring JF, Montgomery J, Gordon MN, Eastman PS, Morgan D (2003) Selectively reduced expression of synaptic plasticity-related genes in amyloid precursor protein + presenilin-1 transgenic mice. J Neurosci 23:5219–5226

    PubMed  CAS  Google Scholar 

  98. Tzingounis AV, Nicoll RA (2006) Arc/Arg3.1: linking gene expression to synaptic plasticity and memory. Neuron 52:403–407

    PubMed  CAS  Google Scholar 

  99. Chowdhury S, Shepherd JD, Okuno H, Lyford G, Petralia RS, Plath N, Kuhl D, Huganir RL, Worley PF (2006) Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking. Neuron 52:445–459

    PubMed  CAS  Google Scholar 

  100. Plath N, Ohana O, Dammermann B, Errington ML, Schmitz D, Gross C, Mao X, Engelsberg A, Mahlke C, Welzl H, Kobalz U, Stawrakakis A, Fernandez E, Waltereit R, Bick-Sander A, Therstappen E, Cooke SF, Blanquet V, Wurst W, Salmen B, Bosl MR, Lipp HP, Grant SG, Bliss TV, Wolfer DP, Kuhl D (2006) Arc/Arg3.1 is essential for the consolidation of synaptic plasticity and memories. Neuron 52:437–444

    PubMed  CAS  Google Scholar 

  101. Shepherd JD, Rumbaugh G, Wu J, Chowdhury S, Plath N, Kuhl D, Huganir RL, Worley PF (2006) Arc/Arg3.1 mediates homeostatic synaptic scaling of AMPA receptors. Neuron 52:475–484

    PubMed  CAS  Google Scholar 

  102. Rial Verde EM, Lee-Osbourne J, Worley PF, Malinow R, Cline HT (2006) Increased expression of the immediate-early gene arc/arg3.1 reduces AMPA receptor-mediated synaptic transmission. Neuron 52:461–474

    PubMed  Google Scholar 

  103. 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 25:9694–9703

    PubMed  CAS  Google Scholar 

  104. 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 25:9686–9693

    PubMed  CAS  Google Scholar 

  105. Ginsberg SD, Hemby SE, Lee VM, Eberwine JH, Trojanowski JQ (2000) Expression profile of transcripts in Alzheimer’s disease tangle-bearing CA1 neurons. Ann Neurol 48:77–87

    PubMed  CAS  Google Scholar 

  106. Maloney MT, Bamburg JR (2007) Cofilin-mediated neurodegeneration in Alzheimer’s disease and other amyloidopathies. Mol Neurobiol 35:21–44

    PubMed  CAS  Google Scholar 

  107. Heredia L, Helguera P, de Olmos S, Kedikian G, Sola Vigo F, LaFerla F, Staufenbiel M, de Olmos J, Busciglio J, Caceres A, Lorenzo A (2006) Phosphorylation of actin-depolymerizing factor/cofilin by LIM-kinase mediates amyloid beta-induced degeneration: a potential mechanism of neuronal dystrophy in Alzheimer’s disease. J Neurosci 26:6533–6542

    PubMed  CAS  Google Scholar 

  108. Gibson PH, Tomlinson BE (1977) Numbers of Hirano bodies in the hippocampus of normal and demented people with Alzheimer’s disease. J Neurol Sci 33:199–206

    PubMed  CAS  Google Scholar 

  109. Chen LY, Rex CS, Casale MS, Gall CM, Lynch G (2007) Changes in synaptic morphology accompany actin signaling during LTP. J Neurosci 27:5363–5372

    PubMed  CAS  Google Scholar 

  110. Fedulov V, Rex CS, Simmons DA, Palmer L, Gall CM, Lynch G (2007) Evidence that long-term potentiation occurs within individual hippocampal synapses during learning. J Neurosci 27:8031–8039

    PubMed  CAS  Google Scholar 

  111. Messaoudi E, Kanhema T, Soule J, Tiron A, Dagyte G, da Silva B, Bramham CR (2007) Sustained Arc/Arg3.1 synthesis controls long-term potentiation consolidation through regulation of local actin polymerization in the dentate gyrus in vivo. J Neurosci 27:10445–10455

    PubMed  CAS  Google Scholar 

  112. Kojima N, Shirao T (2007) Synaptic dysfunction and disruption of postsynaptic drebrin-actin complex: a study of neurological disorders accompanied by cognitive deficits. Neurosci Res 58:1–5

    PubMed  CAS  Google Scholar 

  113. 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 43:633–645

    PubMed  CAS  Google Scholar 

  114. Takahashi H, Mizui T, Shirao T (2006) Down-regulation of drebrin A expression suppresses synaptic targeting of NMDA receptors in developing hippocampal neurones. J Neurochem 97(Suppl 1):110–115

    PubMed  CAS  Google Scholar 

  115. Buttini M, Masliah E, Barbour R, Grajeda H, Motter R, Johnson-Wood K, Khan K, Seubert P, Freedman S, Schenk D, Games D (2005) Beta-amyloid immunotherapy prevents synaptic degeneration in a mouse model of Alzheimer’s disease. J Neurosci 25:9096–90101

    PubMed  CAS  Google Scholar 

  116. De Felice FG, Velasco PT, Lambert MP, Viola K, Fernandez SJ, Ferreira ST, Klein WL (2007) Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J Biol Chem 282:11590–11601

    PubMed  Google Scholar 

  117. Shrestha BR, Vitolo OV, Joshi P, Lordkipanidze T, Shelanski M, Dunaevsky A (2006) Amyloid beta peptide adversely affects spine number and motility in hippocampal neurons. Mol Cell Neurosci 33:274–282

    PubMed  CAS  Google Scholar 

  118. Dineley KT, Hogan D, Zhang WR, Taglialatela G (2007) Acute inhibition of calcineurin restores associative learning and memory in Tg2576 APP transgenic mice. Neurobiol Learn Mem 88:217–224

    PubMed  CAS  Google Scholar 

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Acknowledgements

We would like to thank Professor Roger M. Nitsch, Dr. Uwe Konietzko, and Dr. Luka Kulic for the careful reading of the manuscript and helpful suggestions.

The laboratory of Roger M. Nitsch is supported by the University of Zürich, the Swiss National Science Foundation, the National Center for Competence in Research ‘Neural Plasticity and Repair’, and the Swiss Commission of Technology and Innovation.

The laboratory of Isabelle M. Mansuy is supported by the University of Zürich, the Swiss Federal Institute of Technology, the Swiss National Science Foundation, the National Center for Competence in Research ‘Neural Plasticity and Repair’, the Human Frontier Science Program, EMBO YIP program, the Novartis Research Foundation, and the Slack Gyr Foundation.

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  1. Division of Psychiatry Research, University of Zurich, 8008, Zurich, Switzerland

    Marlen Knobloch

  2. Brain Research Institute, University of Zürich, Department of Biology, Swiss Federal Institute of Technology, 8057, Zürich, Switzerland

    Isabelle M. Mansuy

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  1. Marlen Knobloch
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  2. Isabelle M. Mansuy
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Correspondence to Isabelle M. Mansuy.

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Knobloch, M., Mansuy, I.M. Dendritic Spine Loss and Synaptic Alterations in Alzheimer’s Disease. Mol Neurobiol 37, 73–82 (2008). https://doi.org/10.1007/s12035-008-8018-z

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  • DOI: https://doi.org/10.1007/s12035-008-8018-z

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