Skip to main content

Advertisement

SpringerLink
Log in

Aβ Influences Cytoskeletal Signaling Cascades with Consequences to Alzheimer’s Disease

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Abnormal signal transduction events can impact upon the cytoskeleton, affecting the actin and microtubule networks with direct relevance to Alzheimer’s disease (AD). Cytoskeletal anomalies, in turn, promote atypical neuronal responses, with consequences for cellular organization and function. Neuronal cytoskeletal modifications in AD include neurofibrillary tangles, which result from aggregates of hyperphosphorylated tau protein. The latter is a microtubule (MT)-binding protein, whose abnormal phosphorylation leads to MT instability and consequently provokes irregularities in the neuronal trafficking pathways. Early stages of AD are also characterized by synaptic dysfunction and loss of dendritic spines, which correlate with cognitive deficit and impaired brain function. Actin dynamics has a prominent role in maintaining spine plasticity and integrity, thus providing the basis for memory and learning processes. Hence, factors that disrupt both actin and MT network dynamics will compromise neuronal function and survival. The peptide Aβ is the major component of senile plaques and has been described as a pivotal mediator of neuronal dystrophy and synaptic loss in AD. Here, we review Aβ-mediated effects on both MT and actin networks and focus on the relevance of the elicited cytoskeletal signaling events targeted in AD pathology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Godsel LM, Hobbs RP, Green KJ (2008) Intermediate filament assembly: dynamics to disease. Trends Cell Biol 18(1):28–37. doi:10.1016/j.tcb.2007.11.004

    Article  CAS  PubMed  Google Scholar 

  2. Chang L, Goldman RD (2004) Intermediate filaments mediate cytoskeletal crosstalk. Nat Rev Mol Cell Biol 5(8):601–613. doi:10.1038/nrm1438

    Article  CAS  PubMed  Google Scholar 

  3. Potokar M, Kreft M, Li L, Daniel Andersson J, Pangrsic T, Chowdhury HH, Pekny M, Zorec R (2007) Cytoskeleton and vesicle mobility in astrocytes. Traffic 8(1):12–20. doi:10.1111/j.1600-0854.2006.00509.x

    Article  CAS  PubMed  Google Scholar 

  4. Heidemann SR (1996) Cytoplasmic mechanisms of axonal and dendritic growth in neurons. Int Rev Cytol 165:235–296

    Article  CAS  PubMed  Google Scholar 

  5. Baas PW, Deitch JS, Black MM, Banker GA (1988) Polarity orientation of microtubules in hippocampal neurons: uniformity in the axon and nonuniformity in the dendrite. Proc Natl Acad Sci U S A 85(21):8335–8339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Heidemann SR, Landers JM, Hamborg MA (1981) Polarity orientation of axonal microtubules. J Cell Biol 91(3 Pt 1):661–665

    Article  CAS  PubMed  Google Scholar 

  7. Goedert M, Crowther RA, Garner CC (1991) Molecular characterization of microtubule-associated proteins tau and MAP2. Trends Neurosci 14(5):193–199. doi:10.1016/0166-2236(91)90105-4

    Article  CAS  PubMed  Google Scholar 

  8. Matus A (1988) Microtubule-associated proteins: their potential role in determining neuronal morphology. Annu Rev Neurosci 11:29–44. doi:10.1146/annurev.ne.11.030188.000333

    Article  CAS  PubMed  Google Scholar 

  9. Lewis SA, Wang DH, Cowan NJ (1988) Microtubule-associated protein MAP2 shares a microtubule binding motif with tau protein. Science 242(4880):936–939

    Article  CAS  PubMed  Google Scholar 

  10. Dehmelt L, Halpain S (2005) The MAP2/Tau family of microtubule-associated proteins. Genome Biol 6(1):204. doi:10.1186/gb-2004-6-1-204

    Article  PubMed  Google Scholar 

  11. Alonso AC, Zaidi T, Grundke-Iqbal I, Iqbal K (1994) Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. Proc Natl Acad Sci U S A 91(12):5562–5566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Alonso AD, Grundke-Iqbal I, Barra HS, Iqbal K (1997) Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrillary degeneration: sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau. Proc Natl Acad Sci U S A 94(1):298–303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Alonso AC, Grundke-Iqbal I, Iqbal K (1996) Alzheimer’s disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nat Med 2(7):783–787

    Article  CAS  PubMed  Google Scholar 

  14. Brady ST (1993) Axonal dynamics and regeneration. In: Gorio A (ed) Neuroregeneration. Raven, New York, pp 7–36

    Google Scholar 

  15. Hoogenraad CC, Bradke F (2009) Control of neuronal polarity and plasticity—a renaissance for microtubules? Trends Cell Biol 19(12):669–676. doi:10.1016/j.tcb.2009.08.006S0962-8924(09)00183-4

    Article  CAS  PubMed  Google Scholar 

  16. Gu J, Zheng JQ (2009) Microtubules in dendritic spine development and plasticity. Open Neurosci J 3:128–133. doi:10.2174/1874082000903020128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sakakibara A, Ando R, Sapir T, Tanaka T (2013) Microtubule dynamics in neuronal morphogenesis. Open Biol 3(7):130061. doi:10.1098/rsob.130061

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Priel A, Tuszynski JA, Woolf NJ (2010) Neural cytoskeleton capabilities for learning and memory. J Biol Phys 36(1):3–21. doi:10.1007/s10867-009-9153-0

    Article  CAS  PubMed  Google Scholar 

  19. Kamal A, Stokin GB, Yang Z, Xia CH, Goldstein LS (2000) Axonal transport of amyloid precursor protein is mediated by direct binding to the kinesin light chain subunit of kinesin-I. Neuron 28(2):449–459

    Article  CAS  PubMed  Google Scholar 

  20. Fifkova E, Delay RJ (1982) Cytoplasmic actin in neuronal processes as a possible mediator of synaptic plasticity. J Cell Biol 95(1):345–350

    Article  CAS  PubMed  Google Scholar 

  21. Gordon-Weeks PR (1987) The cytoskeletons of isolated neuronal growth cones. Neuroscience 21(3):977–989

    Article  CAS  PubMed  Google Scholar 

  22. Hirokawa N, Sobue K, Kanda K, Harada A, Yorifuji H (1989) The cytoskeletal architecture of the presynaptic terminal and molecular structure of synapsin 1. J Cell Biol 108(1):111–126

    Article  CAS  PubMed  Google Scholar 

  23. Matus A, Ackermann M, Pehling G, Byers HR, Fujiwara K (1982) High actin concentrations in brain dendritic spines and postsynaptic densities. Proc Natl Acad Sci U S A 79(23):7590–7594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Cohen RS, Chung SK, Pfaff DW (1985) Immunocytochemical localization of actin in dendritic spines of the cerebral cortex using colloidal gold as a probe. Cell Mol Neurobiol 5(3):271–284

    Article  CAS  PubMed  Google Scholar 

  25. dos Remedios CG, Chhabra D, Kekic M, Dedova IV, Tsubakihara M, Berry DA, Nosworthy NJ (2003) Actin binding proteins: regulation of cytoskeletal microfilaments. Physiol Rev 83(2):433–473. doi:10.1152/physrev.00026.2002

    Article  PubMed  Google Scholar 

  26. Luo L (2002) Actin cytoskeleton regulation in neuronal morphogenesis and structural plasticity. Annu Rev Cell Dev Biol 18:601–635. doi:10.1146/annurev.cellbio.18.031802.150501

    Article  CAS  PubMed  Google Scholar 

  27. Ridley AJ, Paterson HF, Johnston CL, Diekmann D, Hall A (1992) The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell 70(3):401–410. doi:10.1016/0092-8674(92)90164-8

    Article  CAS  PubMed  Google Scholar 

  28. Kozma R, Ahmed S, Best A, Lim L (1995) The Ras-related protein Cdc42Hs and bradykinin promote formation of peripheral actin microspikes and filopodia in Swiss 3T3 fibroblasts. Mol Cell Biol 15(4):1942–1952

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nobes CD, Hall A (1995) Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell 81(1):53–62. doi:10.1016/0092-8674(95)90370-4

    Article  CAS  PubMed  Google Scholar 

  30. Bishop AL, Hall A (2000) Rho GTPases and their effector proteins. Biochem J 348(Pt 2):241–255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bourne HR, Sanders DA, McCormick F (1990) The GTPase superfamily: a conserved switch for diverse cell functions. Nature 348(6297):125–132. doi:10.1038/348125a0

    Article  CAS  PubMed  Google Scholar 

  32. Nobes CD, Hall A (1999) Rho GTPases control polarity, protrusion, and adhesion during cell movement. J Cell Biol 144(6):1235–1244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Settleman J (1999) Rho GTPases in development. Prog Mol Subcell Biol 22:201–229

    Article  CAS  PubMed  Google Scholar 

  34. Luo L, Jan LY, Jan YN (1997) Rho family small GTP-binding proteins in growth cone signalling. Curr Opin Neurobiol 7(1):81–86

    Article  CAS  PubMed  Google Scholar 

  35. Lin WH, Webb DJ (2009) Actin and actin-binding proteins: masters of dendritic spine formation, morphology, and function. Open Neurosci J 3:54–66. doi:10.2174/1874082000903020054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Carlier MF, Laurent V, Santolini J, Melki R, Didry D, Xia GX, Hong Y, Chua NH, Pantaloni D (1997) Actin depolymerizing factor (ADF/cofilin) enhances the rate of filament turnover: implication in actin-based motility. J Cell Biol 136(6):1307–1322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Andrianantoandro E, Pollard TD (2006) Mechanism of actin filament turnover by severing and nucleation at different concentrations of ADF/cofilin. Mol Cell 24(1):13–23. doi:10.1016/j.molcel.2006.08.006

    Article  CAS  PubMed  Google Scholar 

  38. Bamburg JR, Bernstein BW (2010) Roles of ADF/cofilin in actin polymerization and beyond. F1000 Biol Rep 2:62. doi:10.3410/B2-62

    PubMed  PubMed Central  Google Scholar 

  39. McGough A, Pope B, Chiu W, Weeds A (1997) Cofilin changes the twist of F-actin: implications for actin filament dynamics and cellular function. J Cell Biol 138(4):771–781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Takahashi H, Sekino Y, Tanaka S, Mizui T, Kishi S, Shirao T (2003) Drebrin-dependent actin clustering in dendritic filopodia governs synaptic targeting of postsynaptic density-95 and dendritic spine morphogenesis. J Neurosci: Offi J Soc Neurosci 23(16):6586–6595

    CAS  Google Scholar 

  41. Mammoto A, Sasaki T, Asakura T, Hotta I, Imamura H, Takahashi K, Matsuura Y, Shirao T, Takai Y (1998) Interactions of drebrin and gephyrin with profilin. Biochem Biophys Res Commun 243(1):86–89. doi:10.1006/bbrc.1997.8068

    Article  CAS  PubMed  Google Scholar 

  42. 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(2):234–242. doi:10.1038/nn1630

    Article  CAS  PubMed  Google Scholar 

  43. Dillon C, Goda Y (2005) The actin cytoskeleton: integrating form and function at the synapse. Annu Rev Neurosci 28:25–55. doi:10.1146/annurev.neuro.28.061604.135757

    Article  CAS  PubMed  Google Scholar 

  44. Halpain S (2003) Actin in a supporting role. Nat Neurosci 6(2):101–102. doi:10.1038/nn0203-101

    Article  CAS  PubMed  Google Scholar 

  45. Zhang W, Benson DL (2001) Stages of synapse development defined by dependence on F-actin. J Neurosci: Offi J Soc Neurosci 21(14):5169–5181

    CAS  Google Scholar 

  46. Schubert V, Dotti CG (2007) Transmitting on actin: synaptic control of dendritic architecture. J Cell Sci 120(Pt 2):205–212. doi:10.1242/jcs.03337

    Article  CAS  PubMed  Google Scholar 

  47. Sekino Y, Kojima N, Shirao T (2007) Role of actin cytoskeleton in dendritic spine morphogenesis. Neurochem Int 51(2–4):92–104. doi:10.1016/j.neuint.2007.04.029

    Article  CAS  PubMed  Google Scholar 

  48. Honkura N, Matsuzaki M, Noguchi J, Ellis-Davies GC, Kasai H (2008) The subspine organization of actin fibers regulates the structure and plasticity of dendritic spines. Neuron 57(5):719–729. doi:10.1016/j.neuron.2008.01.013S0896-6273(08)00074-3

    Article  CAS  PubMed  Google Scholar 

  49. Okamoto K, Nagai T, Miyawaki A, Hayashi Y (2004) Rapid and persistent modulation of actin dynamics regulates postsynaptic reorganization underlying bidirectional plasticity. Nat Neurosci 7(10):1104–1112. doi:10.1038/nn1311

    Article  CAS  PubMed  Google Scholar 

  50. Star EN, Kwiatkowski DJ, Murthy VN (2002) Rapid turnover of actin in dendritic spines and its regulation by activity. Nat Neurosci 5(3):239–246. doi:10.1038/nn811

    Article  CAS  PubMed  Google Scholar 

  51. Haroutunian V, Perl DP, Purohit DP, Marin D, Khan K, Lantz M, Davis KL, Mohs RC (1998) Regional distribution of neuritic plaques in the nondemented elderly and subjects with very mild Alzheimer disease. Arch Neurol 55(9):1185–1191

    Article  CAS  PubMed  Google Scholar 

  52. Yamaguchi H, Hirai S, Morimatsu M, Shoji M, Ihara Y (1988) A variety of cerebral amyloid deposits in the brains of the Alzheimer-type dementia demonstrated by beta protein immunostaining. Acta Neuropathol 76(6):541–549

    Article  CAS  PubMed  Google Scholar 

  53. Kidd M (1963) Paired helical filaments in electron microscopy of Alzheimer’s disease. Nature 197:192–193

    Article  CAS  PubMed  Google Scholar 

  54. Haroutunian V, Purohit DP, Perl DP, Marin D, Khan K, Lantz M, Davis KL, Mohs RC (1999) Neurofibrillary tangles in nondemented elderly subjects and mild Alzheimer disease. Arch Neurol 56(6):713–718

    Article  CAS  PubMed  Google Scholar 

  55. Glenner GG, Wong CW (1984) Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120(3):885–890

    Article  CAS  PubMed  Google Scholar 

  56. Haass C, Kaether C, Thinakaran G, Sisodia S (2012) Trafficking and proteolytic processing of APP. Cold Spring Harb Perspect Med 2(5):a006270. doi:10.1101/cshperspect.a006270

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. da Cruz e Silva EF, da Cruz e Silva OA (2003) Protein phosphorylation and APP metabolism. Neurochem Res 28(10):1553–1561

    Article  CAS  PubMed  Google Scholar 

  58. Rebelo S, Vieira SI, Esselmann H, Wiltfang J, da Cruz e Silva EF, da Cruz e Silva OA (2007) Tyr687 dependent APP endocytosis and Abeta production. J Mol Neurosci: MN 32(1):1–8

    Article  CAS  PubMed  Google Scholar 

  59. Henriques AG, Domingues SC, Fardilha M, da Cruz e Silva EF, da Cruz e Silva OA (2005) Sodium azide and 2-deoxy-D-glucose-induced cellular stress affects phosphorylation-dependent AbetaPP processing. J Alzheimer’s Dis: JAD 7(3):201–212, discussion 255–262

    CAS  PubMed  Google Scholar 

  60. da Cruz e Silva OA, Fardilha M, Henriques AG, Rebelo S, Vieira S, da Cruz e Silva EF (2004) Signal transduction therapeutics: relevance for Alzheimer’s disease. J Mol Neurosci: MN 23(1–2):123–142. doi:10.1385/JMN:23:1–2:123

    Article  CAS  PubMed  Google Scholar 

  61. Jarrett JT, Berger EP, Lansbury PT (1993) The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer’s disease. Biochemistry 32(18):4693–4697

    Article  CAS  PubMed  Google Scholar 

  62. Bitan G, Kirkitadze MD, Lomakin A, Vollers SS, Benedek GB, Teplow DB (2003) Amyloid beta-protein (Abeta) assembly: Abeta 40 and Abeta 42 oligomerize through distinct pathways. Proc Natl Acad Sci U S A 100(1):330–335. doi:10.1073/pnas.222681699

    Article  CAS  PubMed  Google Scholar 

  63. Dahlgren KN, Manelli AM, Stine WB Jr, Baker LK, Krafft GA, LaDu MJ (2002) Oligomeric and fibrillar species of amyloid-beta peptides differentially affect neuronal viability. J Biol Chem 277(35):32046–32053. doi:10.1074/jbc.M201750200

    Article  CAS  PubMed  Google Scholar 

  64. Iijima K, Liu HP, Chiang AS, Hearn SA, Konsolaki M, Zhong Y (2004) Dissecting the pathological effects of human Abeta40 and Abeta42 in Drosophila: a potential model for Alzheimer’s disease. Proc Natl Acad Sci U S A 101(17):6623–6628. doi:10.1073/pnas.0400895101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Hardy J (2006) Has the amyloid cascade hypothesis for Alzheimer’s disease been proved? Curr Alzheimer Res 3(1):71–73

    Article  CAS  PubMed  Google Scholar 

  66. Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256(5054):184–185

    Article  CAS  PubMed  Google Scholar 

  67. Forloni G, Chiesa R, Smiroldo S, Verga L, Salmona M, Tagliavini F, Angeretti N (1993) Apoptosis mediated neurotoxicity induced by chronic application of beta amyloid fragment 25-35. Neuroreport 4(5):523–526

    Article  CAS  PubMed  Google Scholar 

  68. Stadelmann C, Deckwerth TL, Srinivasan A, Bancher C, Bruck W, Jellinger K, Lassmann H (1999) Activation of caspase-3 in single neurons and autophagic granules of granulovacuolar degeneration in Alzheimer’s disease. Evidence for apoptotic cell death. Am J Pathol 155(5):1459–1466. doi:10.1016/S0002-9440(10)65460-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Readnower RD, Sauerbeck AD, Sullivan PG (2011) Mitochondria, amyloid beta, and alzheimer’s disease. Int J Alzheimers Dis 2011:104545. doi:10.4061/2011/104545

  70. Xie CW (2004) Calcium-regulated signaling pathways: role in amyloid beta-induced synaptic dysfunction. Neruomol Med 6(1):53–64. doi:10.1385/NMM:6:1:053

    Article  CAS  Google Scholar 

  71. Davis-Salinas J, Saporito-Irwin SM, Cotman CW, Van Nostrand WE (1995) Amyloid beta-protein induces its own production in cultured degenerating cerebrovascular smooth muscle cells. J Neurochem 65(2):931–934

    Article  CAS  PubMed  Google Scholar 

  72. Schmitt TL, Steiner E, Trieb K, Grubeck-Loebenstein B (1997) Amyloid beta-protein(25-35) increases cellular APP and inhibits the secretion of APPs in human extraneuronal cells. Exp Cell Res 234(2):336–340. doi:10.1006/excr.1997.3606

    Article  CAS  PubMed  Google Scholar 

  73. Carlson CD, Czilli DL, Gitter BD (2000) Regulation of amyloid precursor protein processing by Abeta in human glioma cells. Neurobiol Aging 21(5):747–756

    Article  CAS  PubMed  Google Scholar 

  74. Henriques AG, Vieira SI, Crespo-Lopez ME, de Guiomar de Oliveira MA, da Cruz e Silva EF, da Cruz e Silva OA (2009) Intracellular sAPP retention in response to Abeta is mapped to cytoskeleton-associated structures. J Neurosci Res 87(6):1449–1461. doi:10.1002/jnr.21959

    Article  CAS  PubMed  Google Scholar 

  75. Henriques AG, Vieira SI, da Cruz ESEF, da Cruz ESOA (2010) Abeta promotes Alzheimer’s disease-like cytoskeleton abnormalities with consequences to APP processing in neurons. J Neurochem 113(3):761–771. doi:10.1111/j.1471-4159.2010.06643.x

    Article  CAS  PubMed  Google Scholar 

  76. Tabaton M, Zhu X, Perry G, Smith MA, Giliberto L (2010) Signaling effect of amyloid-beta(42) on the processing of AbetaPP. Exp Neurol 221(1):18–25. doi:10.1016/j.expneurol.2009.09.002

    Article  CAS  PubMed  Google Scholar 

  77. Chung SH (2009) Aberrant phosphorylation in the pathogenesis of Alzheimer’s disease. BMB Rep 42(8):467–474

    Article  CAS  PubMed  Google Scholar 

  78. Vintem AP, Henriques AG, da Cruz ESOA, da Cruz ESEF (2009) PP1 inhibition by Abeta peptide as a potential pathological mechanism in Alzheimer’s disease. Neurotoxicol Teratol 31(2):85–88. doi:10.1016/j.ntt.2008.11.001

    Article  CAS  PubMed  Google Scholar 

  79. Mitsuyama F, Futatsugi Y, Okuya M, Karagiozov K, Peev N, Kato Y, Kanno T, Sano H, Koide T (2009) Amyloid beta: a putative intra-spinal microtubule-depolymerizer to induce synapse-loss or dentritic spine shortening in Alzheimer’s disease. Ital J Anat Embryol 114(2–3):109–120

    PubMed  Google Scholar 

  80. Pike CJ, Cummings BJ, Cotman CW (1992) beta-Amyloid induces neuritic dystrophy in vitro: similarities with Alzheimer pathology. Neuroreport 3(9):769–772

    Article  CAS  PubMed  Google Scholar 

  81. Zempel H, Mandelkow EM (2012) Linking amyloid-beta and tau: amyloid-beta induced synaptic dysfunction via local wreckage of the neuronal cytoskeleton. Neurodegener Dis 10(1–4):64–72. doi:10.1159/000332816

    Article  CAS  PubMed  Google Scholar 

  82. Henriques AG, Vieira SI, da Cruz e Silva OAB (2012) Abeta induces abnormal cytoskeletal dynamics which are reversible upon peptide removal. Microsc Microanal 18(Suppl. 5):23–24

  83. Goode BL, Denis PE, Panda D, Radeke MJ, Miller HP, Wilson L, Feinstein SC (1997) Functional interactions between the proline-rich and repeat regions of tau enhance microtubule binding and assembly. Mol Biol Cell 8(2):353–365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW (1975) A protein factor essential for microtubule assembly. Proc Natl Acad Sci U S A 72(5):1858–1862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Drewes G, Ebneth A, Mandelkow EM (1998) MAPs, MARKs and microtubule dynamics. Trends Biochem Sci 23(8):307–311

    Article  CAS  PubMed  Google Scholar 

  86. Drouet B, Pincon-Raymond M, Chambaz J, Pillot T (2000) Molecular basis of Alzheimer’s disease. Cell Mol Life Sci 57(5):705–715

    Article  CAS  PubMed  Google Scholar 

  87. Gustke N, Steiner B, Mandelkow EM, Biernat J, Meyer HE, Goedert M, Mandelkow E (1992) The Alzheimer-like phosphorylation of tau protein reduces microtubule binding and involves Ser-Pro and Thr-Pro motifs. FEBS Lett 307(2):199–205. doi:10.1016/0014-5793(92)80767-B

    Article  CAS  PubMed  Google Scholar 

  88. Wang JZ, Xia YY, Grundke-Iqbal I, Iqbal K (2013) Abnormal hyperphosphorylation of tau: sites, regulation, and molecular mechanism of neurofibrillary degeneration. J Alzheimer’s Dis: JAD 33(Suppl 1):123–139. doi:10.3233/JAD-2012-129031

    Google Scholar 

  89. Harada A, Oguchi K, Okabe S, Kuno J, Terada S, Ohshima T, Sato-Yoshitake R, Takei Y, Noda T, Hirokawa N (1994) Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature 369(6480):488–491. doi:10.1038/369488a0

    Article  CAS  PubMed  Google Scholar 

  90. Dawson HN, Ferreira A, Eyster MV, Ghoshal N, Binder LI, Vitek MP (2001) Inhibition of neuronal maturation in primary hippocampal neurons from tau deficient mice. J Cell Sci 114(Pt 6):1179–1187

    CAS  PubMed  Google Scholar 

  91. Fujio K, Sato M, Uemura T, Sato T, Sato-Harada R, Harada A (2007) 14-3-3 proteins and protein phosphatases are not reduced in tau-deficient mice. Neuroreport 18(10):1049–1052. doi:10.1097/WNR.0b013e32818b2a0b

    Article  CAS  PubMed  Google Scholar 

  92. Takei Y, Teng J, Harada A, Hirokawa N (2000) Defects in axonal elongation and neuronal migration in mice with disrupted tau and map1b genes. J Cell Biol 150(5):989–1000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Davis RC, Maloney MT, Minamide LS, Flynn KC, Stonebraker MA, Bamburg JR (2009) Mapping cofilin-actin rods in stressed hippocampal slices and the role of cdc42 in amyloid-beta-induced rods. J Alzheimer’s Dis: JAD 18(1):35–50. doi:10.3233/JAD-2009-1122P3X725N7174P4223

    CAS  PubMed Central  Google Scholar 

  94. Maloney MT, Minamide LS, Kinley AW, Boyle JA, Bamburg JR (2005) Beta-secretase-cleaved amyloid precursor protein accumulates at actin inclusions induced in neurons by stress or amyloid beta: a feedforward mechanism for Alzheimer’s disease. J Neurosci: Offi J Soc Neurosci 25(49):11313–11321

    Article  CAS  Google Scholar 

  95. Minamide LS, Striegl AM, Boyle JA, Meberg PJ, Bamburg JR (2000) Neurodegenerative stimuli induce persistent ADF/cofilin-actin rods that disrupt distal neurite function. Nat Cell Biol 2(9):628–636. doi:10.1038/35023579

    Article  CAS  PubMed  Google Scholar 

  96. Bamburg JR, Bernstein BW, Davis RC, Flynn KC, Goldsbury C, Jensen JR, Maloney MT, Marsden IT, Minamide LS, Pak CW, Shaw AE, Whiteman I, Wiggan O (2010) ADF/Cofilin-actin rods in neurodegenerative diseases. Curr Alzheimer Res 7(3):241–250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Maloney MT, Bamburg JR (2007) Cofilin-mediated neurodegeneration in Alzheimer’s disease and other amyloidopathies. Mol Neurobiol 35(1):21–44

    Article  CAS  PubMed  Google Scholar 

  98. Doussau F, Augustine GJ (2000) The actin cytoskeleton and neurotransmitter release: an overview. Biochimie 82(4):353–363

    Article  CAS  PubMed  Google Scholar 

  99. Gordon-Weeks PR, Fournier AE (2013) Neuronal cytoskeleton in synaptic plasticity and regeneration. J Neurochem. doi:10.1111/jnc.12502

    PubMed  Google Scholar 

  100. Knobloch M, Mansuy IM (2008) Dendritic spine loss and synaptic alterations in Alzheimer’s disease. Mol Neurobiol 37(1):73–82. doi:10.1007/s12035-008-8018-z

    Article  CAS  PubMed  Google Scholar 

  101. Grace EA, Rabiner CA, Busciglio J (2002) Characterization of neuronal dystrophy induced by fibrillar amyloid beta: implications for Alzheimer’s disease. Neuroscience 114(1):265–273

    Article  CAS  PubMed  Google Scholar 

  102. Stokin GB, Goldstein LS (2006) Axonal transport and Alzheimer’s disease. Annu Rev Biochem 75:607–627. doi:10.1146/annurev.biochem.75.103004.142637

    Article  CAS  PubMed  Google Scholar 

  103. Hiruma H, Katakura T, Takahashi S, Ichikawa T, Kawakami T (2003) Glutamate and amyloid beta-protein rapidly inhibit fast axonal transport in cultured rat hippocampal neurons by different mechanisms. J Neurosci: Offi J Soc Neurosci 23(26):8967–8977

    CAS  Google Scholar 

  104. Kasa P, Papp H, Kovacs I, Forgon M, Penke B, Yamaguchi H (2000) Human amyloid-beta1-42 applied in vivo inhibits the fast axonal transport of proteins in the sciatic nerve of rat. Neurosci Lett 278(1–2):117–119

    Article  CAS  PubMed  Google Scholar 

  105. Takashima A, Noguchi K, Michel G, Mercken M, Hoshi M, Ishiguro K, Imahori K (1996) Exposure of rat hippocampal neurons to amyloid beta peptide (25-35) induces the inactivation of phosphatidyl inositol-3 kinase and the activation of tau protein kinase I/glycogen synthase kinase-3 beta. Neurosci Lett 203(1):33–36

    Article  CAS  PubMed  Google Scholar 

  106. Wang ZF, Li HL, Li XC, Zhang Q, Tian Q, Wang Q, Xu H, Wang JZ (2006) Effects of endogenous beta-amyloid overproduction on tau phosphorylation in cell culture. J Neurochem 98(4):1167–1175. doi:10.1111/j.1471-4159.2006.03956.x

    Article  CAS  PubMed  Google Scholar 

  107. Magrane J, Rosen KM, Smith RC, Walsh K, Gouras GK, Querfurth HW (2005) Intraneuronal beta-amyloid expression downregulates the Akt survival pathway and blunts the stress response. J Neurosci: Offi J Soc Neurosci 25(47):10960–10969. doi:10.1523/JNEUROSCI.1723-05.2005

    Article  CAS  Google Scholar 

  108. Alvarez G, Munoz-Montano JR, Satrustegui J, Avila J, Bogonez E, Diaz-Nido J (1999) Lithium protects cultured neurons against beta-amyloid-induced neurodegeneration. FEBS Lett 453(3):260–264

    Article  CAS  PubMed  Google Scholar 

  109. Hong M, Chen DC, Klein PS, Lee VM (1997) Lithium reduces tau phosphorylation by inhibition of glycogen synthase kinase-3. J Biol Chem 272(40):25326–25332

    Article  CAS  PubMed  Google Scholar 

  110. Lovestone S, Reynolds CH, Latimer D, Davis DR, Anderton BH, Gallo JM, Hanger D, Mulot S, Marquardt B, Stabel S et al (1994) Alzheimer’s disease-like phosphorylation of the microtubule-associated protein tau by glycogen synthase kinase-3 in transfected mammalian cells. Curr Biol : CB 4(12):1077–1086

    Article  CAS  PubMed  Google Scholar 

  111. Marwarha G, Dasari B, Prabhakara JP, Schommer J, Ghribi O (2010) β-Amyloid regulates leptin expression and tau phosphorylation through the mTORC1 signaling pathway. J Neurochem 115(2):373–384. doi:10.1111/j.1471-4159.2010.06929.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Takashima A, Honda T, Yasutake K, Michel G, Murayama O, Murayama M, Ishiguro K, Yamaguchi H (1998) Activation of tau protein kinase I/glycogen synthase kinase-3beta by amyloid beta peptide (25-35) enhances phosphorylation of tau in hippocampal neurons. Neurosci Res 31(4):317–323

    Article  CAS  PubMed  Google Scholar 

  113. Song MS, Rauw G, Baker GB, Kar S (2008) Memantine protects rat cortical cultured neurons against beta-amyloid-induced toxicity by attenuating tau phosphorylation. Eur J Neurosci 28(10):1989–2002. doi:10.1111/j.1460-9568.2008.06498.x

    Article  CAS  PubMed  Google Scholar 

  114. Zempel H, Thies E, Mandelkow E, Mandelkow EM (2010) Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J Neurosci: Offi J Soc Neurosci 30(36):11938–11950. doi:10.1523/jneurosci.2357-10.2010

    Article  CAS  Google Scholar 

  115. Yu W, Polepalli J, Wagh D, Rajadas J, Malenka R, Lu B (2012) A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Abeta on synapses and dendritic spines. Hum Mol Genet 21(6):1384–1390. doi:10.1093/hmg/ddr576

    Article  CAS  PubMed  Google Scholar 

  116. Augustinack JC, Schneider A, Mandelkow EM, Hyman BT (2002) Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer’s disease. Acta Neuropathol 103(1):26–35

    Article  CAS  PubMed  Google Scholar 

  117. Drewes G, Trinczek B, Illenberger S, Biernat J, Schmitt-Ulms G, Meyer HE, Mandelkow EM, Mandelkow E (1995) Microtubule-associated protein/microtubule affinity-regulating kinase (p110mark). A novel protein kinase that regulates tau-microtubule interactions and dynamic instability by phosphorylation at the Alzheimer-specific site serine 262. J Biol Chem 270(13):7679–7688

    Article  CAS  PubMed  Google Scholar 

  118. Thornton C, Bright NJ, Sastre M, Muckett PJ, Carling D (2011) AMP-activated protein kinase (AMPK) is a tau kinase, activated in response to amyloid beta-peptide exposure. Biochem J 434(3):503–512. doi:10.1042/BJ20101485

    Article  CAS  PubMed  Google Scholar 

  119. Shoji M, Iwakami N, Takeuchi S, Waragai M, Suzuki M, Kanazawa I, Lippa CF, Ono S, Okazawa H (2000) JNK activation is associated with intracellular beta-amyloid accumulation. Brain Res Mol Brain Res 85(1–2):221–233

    Article  CAS  PubMed  Google Scholar 

  120. Zhu X, Raina AK, Rottkamp CA, Aliev G, Perry G, Boux H, Smith MA (2001) Activation and redistribution of c-jun N-terminal kinase/stress activated protein kinase in degenerating neurons in Alzheimer’s disease. J Neurochem 76(2):435–441

    Article  CAS  PubMed  Google Scholar 

  121. Ma QL, Yang F, Rosario ER, Ubeda OJ, Beech W, Gant DJ, Chen PP, Hudspeth B, Chen C, Zhao Y, Vinters HV, Frautschy SA, Cole GM (2009) Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. J Neurosci: Offi J Soc Neurosci 29(28):9078–9089. doi:10.1523/JNEUROSCI.1071-09.2009 29/28/9078

    Article  CAS  Google Scholar 

  122. Hernandez P, Lee G, Sjoberg M, Maccioni RB (2009) Tau phosphorylation by cdk5 and Fyn in response to amyloid peptide Abeta (25-35): involvement of lipid rafts. J Alzheimer’s Dis: JAD 16(1):149–156. doi:10.3233/JAD-2009-0933

    CAS  PubMed  Google Scholar 

  123. Town T, Zolton J, Shaffner R, Schnell B, Crescentini R, Wu Y, Zeng J, DelleDonne A, Obregon D, Tan J, Mullan M (2002) p35/Cdk5 pathway mediates soluble amyloid-beta peptide-induced tau phosphorylation in vitro. J Neurosci Res 69(3):362–372. doi:10.1002/jnr.10299

    Article  CAS  PubMed  Google Scholar 

  124. Correas I, Diaz-Nido J, Avila J (1992) Microtubule-associated protein tau is phosphorylated by protein kinase C on its tubulin binding domain. J Biol Chem 267(22):15721–15728

    CAS  PubMed  Google Scholar 

  125. Chauhan A, Chauhan VP, Brockerhoff H, Wisniewski HM (1991) Action of amyloid beta-protein on protein kinase C activity. Life Sci 49(21):1555–1562

    Article  CAS  PubMed  Google Scholar 

  126. Kuperstein F, Reiss N, Koudinova N, Yavin E (2001) Biphasic modulation of protein kinase C and enhanced cell toxicity by amyloid beta peptide and anoxia in neuronal cultures. J Neurochem 76(3):758–767

    Article  CAS  PubMed  Google Scholar 

  127. Newton AC (1995) Protein kinase C: structure, function, and regulation. J Biol Chem 270(48):28495–28498

    Article  CAS  PubMed  Google Scholar 

  128. Cole G, Dobkins KR, Hansen LA, Terry RD, Saitoh T (1988) Decreased levels of protein kinase C in Alzheimer brain. Brain Res 452(1–2):165–174

    Article  CAS  PubMed  Google Scholar 

  129. Leroy K, Yilmaz Z, Brion JP (2007) Increased level of active GSK-3beta in Alzheimer’s disease and accumulation in argyrophilic grains and in neurones at different stages of neurofibrillary degeneration. Neuropathol Appl Neurobiol 33(1):43–55. doi:10.1111/j.1365-2990.2006.00795.x

    Article  CAS  PubMed  Google Scholar 

  130. Baudier J, Cole RD (1987) Phosphorylation of tau proteins to a state like that in Alzheimer’s brain is catalyzed by a calcium/calmodulin-dependent kinase and modulated by phospholipids. J Biol Chem 262(36):17577–17583

    CAS  PubMed  Google Scholar 

  131. Singh TJ, Wang JZ, Novak M, Kontzekova E, Grundke-Iqbal I, Iqbal K (1996) Calcium/calmodulin-dependent protein kinase II phosphorylates tau at Ser-262 but only partially inhibits its binding to microtubules. FEBS Lett 387(2–3):145–148. doi:10.1016/0014-5793(96)00485-1

    Article  CAS  PubMed  Google Scholar 

  132. Tardito D, Gennarelli M, Musazzi L, Gesuete R, Chiarini S, Barbiero VS, Rydel RE, Racagni G, Popoli M (2007) Long-term soluble Abeta1-40 activates CaM kinase II in organotypic hippocampal cultures. Neurobiol Aging 28(9):1388–1395. doi:10.1016/j.neurobiolaging.2006.06.012

    Article  CAS  PubMed  Google Scholar 

  133. Bennecib M, Gong CX, Grundke-Iqbal I, Iqbal K (2000) Role of protein phosphatase-2A and -1 in the regulation of GSK-3, cdk5 and cdc2 and the phosphorylation of tau in rat forebrain. FEBS Lett 485(1):87–93

    Article  CAS  PubMed  Google Scholar 

  134. Gong CX, Shaikh S, Wang JZ, Zaidi T, Grundke-Iqbal I, Iqbal K (1995) Phosphatase activity toward abnormally phosphorylated tau: decrease in Alzheimer disease brain. J Neurochem 65(2):732–738

    Article  CAS  PubMed  Google Scholar 

  135. Rahman A, Grundke-Iqbal I, Iqbal K (2005) Phosphothreonine-212 of Alzheimer abnormally hyperphosphorylated tau is a preferred substrate of protein phosphatase-1. Neurochem Res 30(2):277–287

    Article  CAS  PubMed  Google Scholar 

  136. Bennecib M, Gong CX, Grundke-Iqbal I, Iqbal K (2001) Inhibition of PP-2A upregulates CaMKII in rat forebrain and induces hyperphosphorylation of tau at Ser 262/356. FEBS Lett 490(1–2):15–22

    Article  CAS  PubMed  Google Scholar 

  137. Tanaka T, Zhong J, Iqbal K, Trenkner E, Grundke-Iqbal I (1998) The regulation of phosphorylation of tau in SY5Y neuroblastoma cells: the role of protein phosphatases. FEBS Lett 426(2):248–254

    Article  CAS  PubMed  Google Scholar 

  138. Gonzalez-Billault C, Jimenez-Mateos EM, Caceres A, Diaz-Nido J, Wandosell F, Avila J (2004) Microtubule-associated protein 1B function during normal development, regeneration, and pathological conditions in the nervous system. J Neurobiol 58(1):48–59. doi:10.1002/neu.10283

    Article  CAS  PubMed  Google Scholar 

  139. Riederer BM (2007) Microtubule-associated protein 1B, a growth-associated and phosphorylated scaffold protein. Brain Res Bull 71(6):541–558. doi:10.1016/j.brainresbull.2006.11.012

    Article  CAS  PubMed  Google Scholar 

  140. Zervas M, Opitz T, Edelmann W, Wainer B, Kucherlapati R, Stanton PK (2005) Impaired hippocampal long-term potentiation in microtubule-associated protein 1B-deficient mice. J Neurosci Res 82(1):83–92. doi:10.1002/jnr.20624

    Article  CAS  PubMed  Google Scholar 

  141. Billups D, Hanley JG, Orme M, Attwell D, Moss SJ (2000) GABAC receptor sensitivity is modulated by interaction with MAP1B. J Neurosci: Offi J Soc Neurosci 20(23):8643–8650

    CAS  Google Scholar 

  142. Cueille N, Blanc CT, Popa-Nita S, Kasas S, Catsicas S, Dietler G, Riederer BM (2007) Characterization of MAP1B heavy chain interaction with actin. Brain Res Bull 71(6):610–618. doi:10.1016/j.brainresbull.2006.12.003

    Article  CAS  PubMed  Google Scholar 

  143. Seog DH (2004) Glutamate receptor-interacting protein 1 protein binds to the microtubule-associated protein. Biosci Biotechnol Biochem 68(8):1808–1810

    Article  CAS  PubMed  Google Scholar 

  144. Gevorkian G, Gonzalez-Noriega A, Acero G, Ordonez J, Michalak C, Munguia ME, Govezensky T, Cribbs DH, Manoutcharian K (2008) Amyloid-beta peptide binds to microtubule-associated protein 1B (MAP1B). Neurochem Int 52(6):1030–1036. doi:10.1016/j.neuint.2007.10.020

    Article  CAS  PubMed  Google Scholar 

  145. Fifre A, Sponne I, Koziel V, Kriem B, Yen Potin FT, Bihain BE, Olivier JL, Oster T, Pillot T (2006) Microtubule-associated protein MAP1A, MAP1B, and MAP2 proteolysis during soluble amyloid beta-peptide-induced neuronal apoptosis. Synergistic involvement of calpain and caspase-3. J Biol Chem 281:229–240. doi:10.1074/jbc.M507378200

    Article  CAS  PubMed  Google Scholar 

  146. Takahashi RH, Capetillo-Zarate E, Lin MT, Milner TA, Gouras GK (2013) Accumulation of intraneuronal beta-amyloid 42 peptides is associated with early changes in microtubule-associated protein 2 in neurites and synapses. PLoS One 8(1):e51965. doi:10.1371/journal.pone.0051965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Clemmensen C, Aznar S, Knudsen GM, Klein AB (2012) The microtubule-associated protein 1A (MAP1A) is an early molecular target of soluble Abeta-peptide. Cell Mol Neurobiol 32(4):561–566. doi:10.1007/s10571-011-9796-9

    Article  CAS  PubMed  Google Scholar 

  148. Goold RG, Owen R, Gordon-Weeks P, Goold RG, Owen R, Gordon-Weeks PR (1999) Glycogen synthase kinase 3beta phosphorylation of microtubule-associated protein 1B regulates the stability of microtubules in growth cones. J Cell Sci 112(Pt 19):3373–3384

    CAS  PubMed  Google Scholar 

  149. Sanchez C, Perez M, Avila J (2000) GSK3beta-mediated phosphorylation of the microtubule-associated protein 2C (MAP2C) prevents microtubule bundling. Eur J Cell Biol 79(4):252–260

    Article  CAS  PubMed  Google Scholar 

  150. Trivedi N, Marsh P, Goold RG, Wood-Kaczmar A, Gordon-Weeks PR (2005) Glycogen synthase kinase-3beta phosphorylation of MAP1B at Ser1260 and Thr1265 is spatially restricted to growing axons. J Cell Sci 118(Pt 5):993–1005. doi:10.1242/jcs.01697

    Article  CAS  PubMed  Google Scholar 

  151. Illenberger S, Drewes G, Trinczek B, Biernat J, Meyer HE, Olmsted JB, Mandelkow EM, Mandelkow E (1996) Phosphorylation of microtubule-associated proteins MAP2 and MAP4 by the protein kinase p110mark. Phosphorylation sites and regulation of microtubule dynamics. J Biol Chem 271(18):10834–10843

    Article  CAS  PubMed  Google Scholar 

  152. Hoshi M, Akiyama T, Shinohara Y, Miyata Y, Ogawara H, Nishida E, Sakai H (1988) Protein-kinase-C-catalyzed phosphorylation of the microtubule-binding domain of microtubule-associated protein 2 inhibits its ability to induce tubulin polymerization. Eur J Biochem/FEBS 174(2):225–230

    Article  CAS  Google Scholar 

  153. Jameson L, Caplow M (1981) Modification of microtubule steady-state dynamics by phosphorylation of the microtubule-associated proteins. Proc Natl Acad Sci U S A 78(6):3413–3417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Arias C, Sharma N, Davies P, Shafit-Zagardo B (1993) Okadaic acid induces early changes in microtubule-associated protein 2 and tau phosphorylation prior to neurodegeneration in cultured cortical neurons. J Neurochem 61(2):673–682

    Article  CAS  PubMed  Google Scholar 

  155. Gong CX, Wegiel J, Lidsky T, Zuck L, Avila J, Wisniewski HM, Grundke-Iqbal I, Iqbal K (2000) Regulation of phosphorylation of neuronal microtubule-associated proteins MAP1b and MAP2 by protein phosphatase-2A and -2B in rat brain. Brain Res 853(2):299–309

    Article  CAS  PubMed  Google Scholar 

  156. Ulloa L, Dombradi V, Diaz-Nido J, Szucs K, Gergely P, Friedrich P, Avila J (1993) Dephosphorylation of distinct sites on microtubule-associated protein MAP1B by protein phosphatases 1, 2A and 2B. FEBS Lett 330(1):85–89

    Article  CAS  PubMed  Google Scholar 

  157. Gong CX, Singh TJ, Grundke-Iqbal I, Iqbal K (1993) Phosphoprotein phosphatase activities in Alzheimer disease brain. J Neurochem 61(3):921–927

    Article  CAS  PubMed  Google Scholar 

  158. Liu F, Grundke-Iqbal I, Iqbal K, Gong CX (2005) Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. Eur J Neurosci 22(8):1942–1950. doi:10.1111/j.1460-9568.2005.04391.x

    Article  PubMed  Google Scholar 

  159. Lehotzky A, Lau P, Tokesi N, Muja N, Hudson LD, Ovadi J (2010) Tubulin polymerization-promoting protein (TPPP/p25) is critical for oligodendrocyte differentiation. Glia 58(2):157–168. doi:10.1002/glia.20909

    Article  PubMed  PubMed Central  Google Scholar 

  160. Kovacs GG, Laszlo L, Kovacs J, Jensen PH, Lindersson E, Botond G, Molnar T, Perczel A, Hudecz F, Mezo G, Erdei A, Tirian L, Lehotzky A, Gelpi E, Budka H, Ovadi J (2004) Natively unfolded tubulin polymerization promoting protein TPPP/p25 is a common marker of alpha-synucleinopathies. Neurobiol Dis 17(2):155–162. doi:10.1016/j.nbd.2004.06.006

    Article  CAS  PubMed  Google Scholar 

  161. Oláh J, Vincze O, Virok D, Simon D, Bozso Z, Tokesi N, Horvath I, Hlavanda E, Kovacs J, Magyar A, Szucs M, Orosz F, Penke B, Ovadi J (2011) Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein. J Biol Chem 286(39):34088–34100. doi:10.1074/jbc.M111.243907

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. Inagaki N, Chihara K, Arimura N, Menager C, Kawano Y, Matsuo N, Nishimura T, Amano M, Kaibuchi K (2001) CRMP-2 induces axons in cultured hippocampal neurons. Nat Neurosci 4(8):781–782. doi:10.1038/90476

    Article  CAS  PubMed  Google Scholar 

  163. Petratos S, Li QX, George AJ, Hou X, Kerr ML, Unabia SE, Hatzinisiriou I, Maksel D, Aguilar MI, Small DH (2008) The beta-amyloid protein of Alzheimer’s disease increases neuronal CRMP-2 phosphorylation by a Rho-GTP mechanism. Brain 131(Pt 1):90–108. doi:10.1093/brain/awm260

    PubMed  Google Scholar 

  164. Fukata Y, Itoh TJ, Kimura T, Menager C, Nishimura T, Shiromizu T, Watanabe H, Inagaki N, Iwamatsu A, Hotani H, Kaibuchi K (2002) CRMP-2 binds to tubulin heterodimers to promote microtubule assembly. Nat Cell Biol 4(8):583–591. doi:10.1038/ncb825

    CAS  PubMed  Google Scholar 

  165. Uchida Y, Ohshima T, Sasaki Y, Suzuki H, Yanai S, Yamashita N, Nakamura F, Takei K, Ihara Y, Mikoshiba K, Kolattukudy P, Honnorat J, Goshima Y (2005) Semaphorin3A signalling is mediated via sequential Cdk5 and GSK3beta phosphorylation of CRMP2: implication of common phosphorylating mechanism underlying axon guidance and Alzheimer’s disease. Gene Cells : Devoted Mol Cell Mech 10(2):165–179. doi:10.1111/j.1365-2443.2005.00827.x

    Article  CAS  Google Scholar 

  166. Yoshimura T, Kawano Y, Arimura N, Kawabata S, Kikuchi A, Kaibuchi K (2005) GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity. Cell 120(1):137–149. doi:10.1016/j.cell.2004.11.012

    Article  CAS  PubMed  Google Scholar 

  167. Black MM, Baas PW, Humphries S (1989) Dynamics of alpha-tubulin deacetylation in intact neurons. J Neurosci: Offi J Soc Neurosci 9(1):358–368

    CAS  Google Scholar 

  168. Black MM, Keyser P (1987) Acetylation of alpha-tubulin in cultured neurons and the induction of alpha-tubulin acetylation in PC12 cells by treatment with nerve growth factor. J Neurosci: Offi J Soc Neurosci 7(6):1833–1842

    CAS  Google Scholar 

  169. Bulinski JC (2007) Microtubule modification: acetylation speeds anterograde traffic flow. Current Biol : CB 17(1):R18–R20. doi:10.1016/j.cub.2006.11.036

    Article  CAS  Google Scholar 

  170. Dompierre JP, Godin JD, Charrin BC, Cordelieres FP, King SJ, Humbert S, Saudou F (2007) Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington’s disease by increasing tubulin acetylation. J Neurosci: Offi J Soc Neurosci 27(13):3571–3583. doi:10.1523/JNEUROSCI.0037-07.2007

    Article  CAS  Google Scholar 

  171. Reed NA, Cai D, Blasius TL, Jih GT, Meyhofer E, Gaertig J, Verhey KJ (2006) Microtubule acetylation promotes kinesin-1 binding and transport. Current Biol : CB 16(21):2166–2172. doi:10.1016/j.cub.2006.09.014

    Article  CAS  PubMed  Google Scholar 

  172. Lippa CF, Hamos JE, Pulaski-Salo D, DeGennaro LJ, Drachman DA (1992) Alzheimer’s disease and aging: effects on perforant pathway perikarya and synapses. Neurobiol Aging 13(3):405–411

    Article  CAS  PubMed  Google Scholar 

  173. Masliah E (1995) Mechanisms of synaptic dysfunction in Alzheimer’s disease. Histol Histopathol 10(2):509–519

    CAS  PubMed  Google Scholar 

  174. Halpain S (2000) Actin and the agile spine: how and why do dendritic spines dance. Trends Neurosci 23(4):141–146

    Article  CAS  PubMed  Google Scholar 

  175. Matus A, Brinkhaus H, Wagner U (2000) Actin dynamics in dendritic spines: a form of regulated plasticity at excitatory synapses. Hippocampus 10(5):555–560. doi:10.1002/1098-1063(2000)10:5<555::AID-HIPO5>3.0.CO;2-Z

    Article  CAS  PubMed  Google Scholar 

  176. Takahashi RH, Almeida CG, Kearney PF, Yu F, Lin MT, Milner TA, Gouras GK (2004) Oligomerization of Alzheimer’s beta-amyloid within processes and synapses of cultured neurons and brain. J Neurosci: Offi J Soc Neurosci 24(14):3592–3599. doi:10.1523/JNEUROSCI.5167-03.2004

    Article  CAS  Google Scholar 

  177. Song C, Perides G, Wang D, Liu YF (2002) beta-Amyloid peptide induces formation of actin stress fibers through p38 mitogen-activated protein kinase. J Neurochem 83(4):828–836

    Article  CAS  PubMed  Google Scholar 

  178. Huot J, Houle F, Rousseau S, Deschesnes RG, Shah GM, Landry J (1998) SAPK2/p38-dependent F-actin reorganization regulates early membrane blebbing during stress-induced apoptosis. J Cell Biol 143(5):1361–1373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Kim E, Naisbitt S, Hsueh YP, Rao A, Rothschild A, Craig AM, Sheng M (1997) GKAP, a novel synaptic protein that interacts with the guanylate kinase-like domain of the PSD-95/SAP90 family of channel clustering molecules. J Cell Biol 136(3):669–678

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Roselli F, Livrea P, Almeida OF (2011) CDK5 is essential for soluble amyloid beta-induced degradation of GKAP and remodeling of the synaptic actin cytoskeleton. PLoS One 6(7):e23097. doi:10.1371/journal.pone.0023097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Edwards DC, Sanders LC, Bokoch GM, Gill GN (1999) Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics. Nat Cell Biol 1(5):253–259. doi:10.1038/12963

    Article  CAS  PubMed  Google Scholar 

  182. Ohashi K, Nagata K, Maekawa M, Ishizaki T, Narumiya S, Mizuno K (2000) Rho-associated kinase ROCK activates LIM-kinase 1 by phosphorylation at threonine 508 within the activation loop. J Biol Chem 275(5):3577–3582

    Article  CAS  PubMed  Google Scholar 

  183. Mendoza-Naranjo A, Gonzalez-Billault C, Maccioni RB (2007) Abeta1-42 stimulates actin polymerization in hippocampal neurons through Rac1 and Cdc42 Rho GTPases. J Cell Sci 120(Pt 2):279–288. doi:10.1242/jcs.03323

    Article  CAS  PubMed  Google Scholar 

  184. Habets GG, Scholtes EH, Zuydgeest D, van der Kammen RA, Stam JC, Berns A, Collard JG (1994) Identification of an invasion-inducing gene, Tiam-1, that encodes a protein with homology to GDP-GTP exchangers for Rho-like proteins. Cell 77(4):537–549. doi:10.1016/0092-8674(94)90216-x

    Article  CAS  PubMed  Google Scholar 

  185. 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(1–2):199–206

    Article  CAS  PubMed  Google Scholar 

  186. Ma QL, Yang F, Calon F, Ubeda OJ, Hansen JE, Weisbart RH, Beech W, Frautschy SA, Cole GM (2008) p21-activated kinase-aberrant activation and translocation in Alzheimer disease pathogenesis. J Biol Chem 283(20):14132–14143. doi:10.1074/jbc.M708034200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Nakayama AY, Harms MB, Luo L (2000) Small GTPases Rac and Rho in the maintenance of dendritic spines and branches in hippocampal pyramidal neurons. J Neurosci: Offi J Soc Neurosci 20(14):5329–5338

    CAS  Google Scholar 

  188. Zhu X, Raina AK, Boux H, Simmons ZL, Takeda A, Smith MA (2000) Activation of oncogenic pathways in degenerating neurons in Alzheimer disease. Int J Dev Neurosci 18(4–5):433–437

    Article  CAS  PubMed  Google Scholar 

  189. Huesa G, Baltrons MA, Gomez-Ramos P, Moran A, Garcia A, Hidalgo J, Frances S, Santpere G, Ferrer I, Galea E (2010) Altered distribution of RhoA in Alzheimer’s disease and AbetaPP overexpressing mice. J Alzheimer’s Dis: JAD 19(1):37–56. doi:10.3233/JAD-2010-1203

    PubMed  Google Scholar 

  190. 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: Offi J Soc Neurosci 26(24):6533–6542. doi:10.1523/JNEUROSCI.5567-05.2006

    Article  CAS  Google Scholar 

  191. Mendoza-Naranjo A, Contreras-Vallejos E, Henriquez DR, Otth C, Bamburg JR, Maccioni RB, Gonzalez-Billault C (2012) Fibrillar amyloid-beta1-42 modifies actin organization affecting the cofilin phosphorylation state: a role for Rac1/cdc42 effector proteins and the slingshot phosphatase. J Alzheimer’s Dis: JAD 29(1):63–77. doi:10.3233/JAD-2012-101575

    CAS  PubMed  Google Scholar 

  192. Grace EA, Busciglio J (2003) Aberrant activation of focal adhesion proteins mediates fibrillar amyloid beta-induced neuronal dystrophy. J Neurosci: Offi J Soc Neurosci 23(2):493–502

    CAS  Google Scholar 

  193. Chen GC, Turano B, Ruest PJ, Hagel M, Settleman J, Thomas SM (2005) Regulation of Rho and Rac signaling to the actin cytoskeleton by paxillin during Drosophila development. Mol Cell Biol 25(3):979–987. doi:10.1128/MCB.25.3.979-987.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Foletta VC, Moussi N, Sarmiere PD, Bamburg JR, Bernard O (2004) LIM kinase 1, a key regulator of actin dynamics, is widely expressed in embryonic and adult tissues. Exp Cell Res 294(2):392–405. doi:10.1016/j.yexcr.2003.11.024

    Article  CAS  PubMed  Google Scholar 

  195. Fleming IN, Elliott CM, Buchanan FG, Downes CP, Exton JH (1999) Ca2+/calmodulin-dependent protein kinase II regulates Tiam1 by reversible protein phosphorylation. J Biol Chem 274(18):12753–12758

    Article  CAS  PubMed  Google Scholar 

  196. Gu Z, Zhong P, Yan Z (2003) Activation of muscarinic receptors inhibits beta-amyloid peptide-induced signaling in cortical slices. J Biol Chem 278(19):17546–17556. doi:10.1074/jbc.M209892200

    Article  CAS  PubMed  Google Scholar 

  197. Lee W, Boo JH, Jung MW, Park SD, Kim YH, Kim SU, Mook-Jung I (2004) Amyloid beta peptide directly inhibits PKC activation. Mol Cell Neurosci 26(2):222–231. doi:10.1016/j.mcn.2003.10.020

    Article  CAS  PubMed  Google Scholar 

  198. Hull M, Muksch B, Akundi RS, Waschbisch A, Hoozemans JJ, Veerhuis R, Fiebich BL (2006) Amyloid beta peptide (25-35) activates protein kinase C leading to cyclooxygenase-2 induction and prostaglandin E2 release in primary midbrain astrocytes. Neurochem Int 48(8):663–672. doi:10.1016/j.neuint.2005.08.013

    Article  PubMed  CAS  Google Scholar 

  199. Zhao JW, Gao ZL, Ji QY, Wang H, Zhang HY, Yang YD, Xing FJ, Meng LJ, Wang Y (2012) Regulation of cofilin activity by CaMKII and calcineurin. Am J Med Sci 344(6):462–472. doi:10.1097/MAJ.0b013e318244745b

    Article  PubMed  Google Scholar 

  200. Chen TJ, Gehler S, Shaw AE, Bamburg JR, Letourneau PC (2006) Cdc42 participates in the regulation of ADF/cofilin and retinal growth cone filopodia by brain derived neurotrophic factor. J Neurobiol 66(2):103–114. doi:10.1002/neu.20204

    Article  CAS  PubMed  Google Scholar 

  201. Lakshmana MK, Chung JY, Wickramarachchi S, Tak E, Bianchi E, Koo EH, Kang DE (2010) A fragment of the scaffolding protein RanBP9 is increased in Alzheimer’s disease brains and strongly potentiates amyloid-beta peptide generation. FASEB J: Off Publ Fed Am Soc Exp Biol 24(1):119–127. doi:10.1096/fj.09-136457

    Article  CAS  Google Scholar 

  202. Woo JA, Jung AR, Lakshmana MK, Bedrossian A, Lim Y, Bu JH, Park SA, Koo EH, Mook-Jung I, Kang DE (2012) Pivotal role of the RanBP9-cofilin pathway in Abeta-induced apoptosis and neurodegeneration. Cell Death Differ 19(9):1413–1423. doi:10.1038/cdd.2012.14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Domingues SC, Konietzko U, Henriques AG, Rebelo S, Fardilha M, Nishitani H, Nitsch RM, da Cruz ESEF, da Cruz ESOA (2014) RanBP9 modulates AICD localization and transcriptional activity via direct interaction with Tip60. J Alzheimer’s Dis: JAD. doi:10.3233/JAD-132495

    PubMed  Google Scholar 

  204. Lakshmana MK, Hayes CD, Bennett SP, Bianchi E, Reddy KM, Koo EH, Kang DE (2012) Role of RanBP9 on amyloidogenic processing of APP and synaptic protein levels in the mouse brain. FASEB J: Off Publ Fed Am Soc Exp Biol 26(5):2072–2083. doi:10.1096/fj.11-196709

    Article  CAS  Google Scholar 

  205. Lakshmana MK, Yoon IS, Chen E, Bianchi E, Koo EH, Kang DE (2009) Novel role of RanBP9 in BACE1 processing of amyloid precursor protein and amyloid beta peptide generation. J Biol Chem 284(18):11863–11872. doi:10.1074/jbc.M807345200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Davis RC, Marsden IT, Maloney MT, Minamide LS, Podlisny M, Selkoe DJ, Bamburg JR (2011) Amyloid beta dimers/trimers potently induce cofilin-actin rods that are inhibited by maintaining cofilin-phosphorylation. Mol Neurodegener 6:10. doi:10.1186/1750-1326-6-10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Wang Y, Shibasaki F, Mizuno K (2005) Calcium signal-induced cofilin dephosphorylation is mediated by Slingshot via calcineurin. J Biol Chem 280(13):12683–12689. doi:10.1074/jbc.M411494200

    Article  CAS  PubMed  Google Scholar 

  208. Xia Z, Storm DR (2005) The role of calmodulin as a signal integrator for synaptic plasticity. Nat Rev Neurosci 6(4):267–276. doi:10.1038/nrn1647

    Article  CAS  PubMed  Google Scholar 

  209. Rozkalne A, Hyman BT, Spires-Jones TL (2011) Calcineurin inhibition with FK506 ameliorates dendritic spine density deficits in plaque-bearing Alzheimer model mice. Neurobiol Dis 41(3):650–654. doi:10.1016/j.nbd.2010.11.014

    Article  CAS  PubMed  Google Scholar 

  210. Wu HY, Hudry E, Hashimoto T, Kuchibhotla K, Rozkalne A, Fan Z, Spires-Jones T, Xie H, Arbel-Ornath M, Grosskreutz CL, Bacskai BJ, Hyman BT (2010) Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation. J Neurosci: Offi J Soc Neurosci 30(7):2636–2649. doi:10.1523/JNEUROSCI.4456-09.2010 30/7/2636

    Article  CAS  Google Scholar 

  211. 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: Offi J Soc Neurosci 27(11):2866–2875. doi:10.1523/JNEUROSCI.4970-06.2007

    Article  CAS  Google Scholar 

  212. 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(5):831–843. doi:10.1016/j.neuron.2006.10.035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Tang W, Zhang Y, Xu W, Harden TK, Sondek J, Sun L, Li L, Wu D (2011) A PLCbeta/PI3Kgamma-GSK3 signaling pathway regulates cofilin phosphatase slingshot2 and neutrophil polarization and chemotaxis. Dev Cell 21(6):1038–1050. doi:10.1016/j.devcel.2011.10.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Manterola L, Hernando-Rodriguez M, Ruiz A, Apraiz A, Arrizabalaga O, Vellon L, Alberdi E, Cavaliere F, Lacerda HM, Jimenez S, Parada LA, Matute C, Zugaza JL (2013) 1-42 beta-amyloid peptide requires PDK1/nPKC/Rac 1 pathway to induce neuronal death. Transl Psychiatry 3:e219. doi:10.1038/tp.2012.147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Ambach A, Saunus J, Konstandin M, Wesselborg S, Meuer SC, Samstag Y (2000) The serine phosphatases PP1 and PP2A associate with and activate the actin-binding protein cofilin in human T lymphocytes. Eur J Immunol 30(12):3422–3431. doi:10.1002/1521-4141(2000012)30:12<3422::AID-IMMU3422>3.0.CO;2-J

    Article  CAS  PubMed  Google Scholar 

  216. da Cruz e Silva EF, Fox CA, Ouimet CC, Gustafson E, Watson SJ, Greengard P (1995) Differential expression of protein phosphatase 1 isoforms in mammalian brain. J Neurosci: Offi J Soc Neurosci 15(5 Pt 1):3375–3389

    CAS  Google Scholar 

  217. Soosairajah J, Maiti S, Wiggan O, Sarmiere P, Moussi N, Sarcevic B, Sampath R, Bamburg JR, Bernard O (2005) Interplay between components of a novel LIM kinase-slingshot phosphatase complex regulates cofilin. EMBO J 24(3):473–486. doi:10.1038/sj.emboj.7600543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was financed by the Fundação para a Ciência e Tecnologia of the Ministério da Educação e Ciência (JPND/0006/2011-BIOMARKAPD), the COMPETE program, QREN, and the European Union (Fundo Europeu de Desenvolvimento Regional) and also supported by PEst-OE/SAU/UI0482/2013.

Author information

Authors and Affiliations

  1. Laboratório de Neurociências e Sinalização, Centro de Biologia Celular, SACS, Universidade de Aveiro, 3810-193, Aveiro, Portugal

    Ana Gabriela Henriques, Joana Machado Oliveira, Liliana Patrícia Carvalho & Odete A. B. da Cruz e Silva

Authors
  1. Ana Gabriela Henriques
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joana Machado Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liliana Patrícia Carvalho
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Odete A. B. da Cruz e Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Odete A. B. da Cruz e Silva.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Henriques, A.G., Oliveira, J.M., Carvalho, L.P. et al. Aβ Influences Cytoskeletal Signaling Cascades with Consequences to Alzheimer’s Disease. Mol Neurobiol 52, 1391–1407 (2015). https://doi.org/10.1007/s12035-014-8913-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-014-8913-4

Keywords

Search

Navigation