Cyclin-Dependent Kinase 5 (Cdk5): Linking Synaptic Plasticity and Neurodegeneration

  • Andre Fischer
  • Li-Huei Tsai


It is well established that cyclin-dependent kinase 5 (Cdk5) is critically involved in neurodevelopmental processes. In addition, recent data point toward an important role of Cdk5 in regulating synaptic plasticity, learning, and memory in the adult brain. However, aberrant Cdk5 activity has been implicated in various neurodegenerative diseases such as Alzheimer’s disease. Deregulation of Cdk5 has been attributed to calpain-mediated cleavage of the Cdk5 activator p35 to the N-terminally truncated p25 protein. p25 levels are elevated in many neurodegenerative diseases and implicated in neuronal cell death in vitro and in vivo. More importantly, p25/Cdk5 causes hyperphosphorylation of tau and affects processing of APP, leading to increased levels of toxic Aβ-peptides. Surprisingly, recent data indicate that in vivo p25 is not toxic per se but that a transient increase in p25 levels may even facilitate neuroplasticity. Here we will review these recent developments and propose a scenario in which p25 generation during aging and Alzheimer’s disease might initially be a compensatory phenomenon to enhance neuroplasticity but eventually contributes to the pathogenesis of Alzheimer’s disease when chronically elevated.


NMDA Receptor Synaptic Plasticity Dendritic Spine Cdk5 Activity Synaptic Vesicle Endocytosis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We would like to thank Dr. Benjamin Samuals, Dr.Farahnaz Sananbenesi, Matthew Dobbin, and Jessica Wittnam for reading the manuscript and critical discussion. This work was supported by a EURYI award to AF. The ENI-Goettingen is jointly funded by the Max Planck Society and the Medical School, Georg-August University, Göttingen, Germany. L-HT is an investigator of the Howard Hughes Medical Institute, RIKEN-MIT Neuroscience Research Center, director of Neurobiology Program at Stanley Center for Psychiatric Research, Cambridge, MA, USA.


  1. Abel, T., Nguyen, P. V., Barad, M., Deuel, T. A., Kandel, E. R., and Bourtchouladze, R. (1997). Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory. Cell 88, 615–626.PubMedGoogle Scholar
  2. Ahlijanian, M. K., Barrezueta, N. X., Williams, R. D., Jakowski, A., Kowsz, K. P., McCarthy, S., Coskran, T., Carlo, A., Seymour, P. A., Burkhardt, J. E., et al. (2000). Hyperphosphorylated tau and neurofilament and cytoskeletal disruptions in mice overexpressing human p25, an activator of cdk5. Proc Natl Acad Sci U S A 97, 2910–2915.PubMedGoogle Scholar
  3. Alberini, C. M. (1999). Genes to remember. J Exp Biol 202, 2887–2891.PubMedGoogle Scholar
  4. Angelo, M., Plattner, F., Irvine, E. E., and Giese, K. P. (2003). Improved reversal learning and altered fear conditioning in transgenic mice with regionally restricted p25 expression. Eur J Neurosci 18, 423–431.PubMedGoogle Scholar
  5. Arber, S., Barbayannis, F. A., H., H., Schneider, C., Stanyon, C. A., Bernard, O., and Caroni, P. (1998). Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase. Nature 393, 739–740.Google Scholar
  6. Arendt, T. (2004). Neurodegeneration and plasticity. Int J Dev Neurosci 22, 507–514.PubMedGoogle Scholar
  7. Armstrong, D. M., Sheffield, R., Mishizen-Eberz, A. J., Carter, T. L., Rissman, R. A., Mizukami, K., and Ikonomovic, M. D. (2003). Plasticity of glutamate and GABAA receptors in the hippocampus of patients with Alzheimer's disease. Cell Mol Neurobiol 23, 491–505.PubMedGoogle Scholar
  8. Atkins, C. M., Selcher, J. C., Petraitis, J. J., Trzaskos, J. M., and Sweatt, J. D. (1998). The MAPK cascade is required for mammalian associative learning. Nat Neurosci 1, 602–609.PubMedGoogle Scholar
  9. Avraham, E., Rott, R., Liani, E., Szargel, R., and Engelender, S. (2007). Phosphorylation of Parkin by the cyclin-dependent kinase 5 at the linker region modulates its ubiquitin-ligase activity and aggregation. J Biol Chem 282, 12842–12850.PubMedGoogle Scholar
  10. Ayala, R., Shu, T., and Tsai, L. H. (2007). Trekking across the brain: the journey of neuronal migration. Cell 128, 29–43.PubMedGoogle Scholar
  11. Bamji, S. X., Shimazu, K., Kimes, N., Huelsken, J., Birchmeier, W., Lu, B., and Reichardt, L. F. (2003). Role of beta-catenin in synaptic vesicle localization and presynaptic assembly. Neuron 40, 719–731.PubMedGoogle Scholar
  12. Barco, A., Bailey, C. H., and Kandel, E. R. (2006). Common molecular mechanisms in explicit and implicit memory. J Neurochem 97, 1520–1533.PubMedGoogle Scholar
  13. Beffert, U., Weeber, E. J., Morfini, G., Ko, J., Brady, S. T., Tsai, L. H., Sweatt, J. D., and Herz, J. (2004). Reelin and cyclin-dependent kinase 5-dependent signals cooperate in regulating neuronal migration and synaptic transmission. J Neurosci 24, 1897–1906.PubMedGoogle Scholar
  14. Bian, F., Nath, R., Sobocinski, G., Booher, R. N., Lipinski, W. J., Callahan, M. J., Pack, A., Wang, K. K., and Walker, L. C. (2002). Axonopathy, tau abnormalities, and dyskinesia, but no neurofibrillary tangles in p25-transgenic mice. J Comp Neurol 446, 257–266.PubMedGoogle Scholar
  15. Bibb, J. A., Chen, J., Taylor, J. R., Svenningsson, P., Nishi, A., Snyder, G. L., Yan, Z., Sagawa, Z. K., Ouimet, C. C., and Nairn, A. C., et al. (2001). Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5. Nature 410, 376–380.PubMedGoogle Scholar
  16. Bonhoeffer, T., and Yuste, R. (2002). Spine motility. Phenomenology, mechanisms, and function. Neuron 35, 1019–1027.PubMedGoogle Scholar
  17. Borghi, R., Giliberto, L., Assini, A., Delacourte, A., Perry, G., Smith, M. A., Strocchi, P., Zaccheo, D., and Tabaton, M. (2002). Increase of cdk5 is related to neurofibrillary pathology in progressive supranuclear palsy. Neurology 58, 589–592.PubMedGoogle Scholar
  18. Brion, J. P., and Couck, A. M. (1995). Cortical and brainstem-type Lewy bodies are immunoreactive for the cyclin-dependent kinase 5. Am J Pathol 147, 1465–1476.PubMedGoogle Scholar
  19. Brose, N. (1999). Synaptic cell adhesion proteins and synaptogenesis in the mammalian central nervous system. Naturwissenschaften 86, 516–524.PubMedGoogle Scholar
  20. Bu, B., Li, J., Davies, P., and Vincent, I. (2002). Deregulation of cdk5, hyperphosphorylation, and cytoskeletal pathology in the Niemann-Pick type C murine model. J Neurosci 22, 6515–6525.PubMedGoogle Scholar
  21. Chae, T., Kwon, Y. T., Bronson, R., Dikkes, P., Li, E., and Tsai, L. H. (1997). Mice lacking p35, a neuronal specific activator of Cdk5, display cortical lamination defects, seizures, and adult lethality. Neuron 18, 29–42.PubMedGoogle Scholar
  22. Cheung, Z. H., Chin, W. H., Chen, Y., Ng, Y. P., and Ip, N. Y. (2007). Cdk5 Is Involved in BDNF-stimulated dendritic growth in hippocampal neurons. PLos Biol 5, e63.PubMedGoogle Scholar
  23. Cheung, Z. H., Fu, A. K., and Ip, N. Y. (2006). Synaptic roles of Cdk5: implications in higher cognitive functions and neurodegenerative diseases. Neuron 50, 13–18.PubMedGoogle Scholar
  24. Cotman, C. W., and Anderson, K. J. (1988). Synaptic plasticity and functional stabilization in the hippocampal formation: possible role in Alzheimer's disease. Adv Neurol 47, 12–35.Google Scholar
  25. Cruz, J. C., Kim, D., Moy, L. Y., Dobbin, M. M., Sun, X., Bronson, R. T., and Tsai, L. H. (2006a). Free Full Text p25/cyclin-dependent kinase 5 induces production and intraneuronal accumulation of amyloid beta in vivo. J Neurosci 26, 10536–10541.Google Scholar
  26. Cruz, J. C., Kim, D., Moy, L. Y., Dobbin, M. M., Sun, X., Bronson, R. T., and Tsai, L. H. (2006b). p25/cyclin-dependent kinase 5 induces production and intraneuronal accumulation of amyloid beta in vivo. J Neurosci 26, 10536–10541.Google Scholar
  27. Cruz, J. C., and Tsai, L. H. (2004). Jekyll and Hyde kinase: roles for Cdk5 in brain development and disease. Curr Opin Neurobiol 14, 390–394.PubMedGoogle Scholar
  28. Cruz, J. C., Tseng, H. C., Goldman, J. A., Shih, H., and Tsai, L. H. (2003). Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron 40, 471–483.PubMedGoogle Scholar
  29. Dhavan, R., Greer, P. L., Morabito, M. A., Orlando, L. R., and Tsai, L. H. (2002a). The cyclin-dependent kinase 5 activators p35 and p39 interact with the alpha-subunit of Ca2+/calmodulin-dependent protein kinase II and alpha-actinin-1 in a calcium-dependent manner. J Neurosci 22, 7879–7891.Google Scholar
  30. Dhavan, R., Greer, P. L., Morabito, M. A., Orlando, L. R., and Tsai, L. H. (2002b). The cyclin-dependent kinase 5 activators p35 and p39 interact with the alpha-subunit of Ca2+/calmodulin-dependent protein kinase II and alpha- actinin-1 in a calcium-dependent manner. J Neurosci 22, 7879–7891.Google Scholar
  31. Dhavan, R., and Tsai, L. H. (2001). A decade of CDK5. Nat Rev Mol Cell Biol 2, 749–759.PubMedGoogle Scholar
  32. Edwards, D. C., Sanders, L. C., Bokoch, G. M., and Gill, G. N. (1999). Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics. Nat Cell Biol 1, 253–259.PubMedGoogle Scholar
  33. Fischer, A., Sananbenesi, F., Pang, P. T., Lu, B., and Tsai, L. H. (2005). Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory. Neuron 48, 825–838.PubMedGoogle Scholar
  34. Fischer, A., Sananbenesi, F., Schrick, C., Spiess, J., and Radulovic, J. (2002). Cyclin-dependent kinase 5 is required for associative learning. J Neurosci 22, 3700–3707.PubMedGoogle Scholar
  35. Fischer, A., Sananbenesi, F., Schrick, C., Spiess, J., and Radulovic, J. (2004). Distinct roles of hippocampal de novo protein synthesis and actin rearrangement in extinction of contextual fear. J Neurosci 24, 1962–1966.PubMedGoogle Scholar
  36. Fischer, A., Sananbenesi, F., Spiess, J., and Radulovic, J. (2003). Cdk5 in the adult non-demented brain. Curr Drug Targets CNS Neurol Disord 6, 375–381.Google Scholar
  37. Fischer, A., Sananbenesi, F., Wang, X., Dobbin, M., and Tsai, L. H. (2007). Recovery of learning and memory after neuronal loss is associated with chromatin remodeling. Nature 447, 178–182PubMedGoogle Scholar
  38. Flavell, S. W., Cowan, C. W., Kim, T. K., Greer, P. L., Lin, Y., Paradis, S., Griffith, E. C., Hu, L. S., Chen, C., and Greenberg, M. E. (2006). Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number. Science 311, 1008–1012.PubMedGoogle Scholar
  39. Fletcher, A. I., Shuang, R., Giovannucci, D. R., Zhang, L., Bittner, M. A., and Stuenkel, E. L. (1999). Regulation of exocytosis by cyclin-dependent kinase 5 via phosphorylation of Munc18. J Biol Chem 274, 4027–4035.PubMedGoogle Scholar
  40. Floyd, S. R., Porro, E. B., Slepnev, V. I., Ochoa, G. C., Tsai, L. H., and De Camilli, P. (2001). Amphiphysin 1 binds the cyclin-dependent kinase (cdk) 5 regulatory subunit p35 and is phosphorylated by cdk5 and cdc2. J Biol Chem 276, 8104–8110.PubMedGoogle Scholar
  41. Frey, U., and Morris, R. G. (1998). Synaptic tagging: implications for late maintenance of hippocampal long-term potentiation. Trends Neurosci 21, 181–188.PubMedGoogle Scholar
  42. Fu, A. K., Fu, W. Y., Cheung, J., Tsim, K. W., Fanny, F. C. Ip., Wang, J. H., and Ip, N. Y. (2001). Cdk5 is involved in neuregulin-induced AChR expression at the neuromuscular junction. Nat Neurosci 4, 374–381.PubMedGoogle Scholar
  43. Fu, W. Y., Chen, Y., Sahin, M., Zhao, X. S., Shi, L., Bikoff, J. B., Lai, K. O., Yung, W. H., Fu, A. K., Greenberg, M. E., and Ip, N. Y.. (2007). Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism. Nat Neurosci 10, 67–76.PubMedGoogle Scholar
  44. Gong, X., Tang, X., Wiedmann, M., Wang, X., Peng, J., Zheng, D., Blair, L. A., Marshall, J., and Mao, Z. (2003). Cdk5-mediated inhibition of the protective effects of transcription factor MEF2 in neurotoxicity-induced apoptosis. Neuron 38, 33–46.PubMedGoogle Scholar
  45. Govindarajan, A., Kelleher, R. J., and Tonegawa, S. (2006). A clustered plasticity model of long-term memory engrams. Nat Rev Neurosci 7, 575–583.PubMedGoogle Scholar
  46. Hallows, J. L., Iosif, R. E., Biasell, R. D., and Vincent, I. (2006). p35/p25 is not essential for tau and cytoskeletal pathology or neuronal loss in Niemann-Pick type C disease. J Neurosci 26, 2738–2744.PubMedGoogle Scholar
  47. Halpain, S. (2000). Actin and the agile spine: how and why do dendritic spines dance? Trends Neurosci 23, 141–146.PubMedGoogle Scholar
  48. Hawasli, A. H., Benavides, D. R., Nguyen, C., Kansy, J. W., Hayashi, K., Chambon, P., Greengard, P., Powell, C. M., Cooper, D. C., and Bibb, J. A. (2007). Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation. Nat Neurosci 10,:880–806.PubMedGoogle Scholar
  49. Hayashi, M. L., Choi, S. Y., Rao, B. S., Jung, H. Y., Lee, H. K., Zhang, D., Chattarji, S., Kirkwood, A., and Tonegawa, S. (2004). Altered cortical synaptic morphology and impaired memory consolidation in forebrain- specific dominant-negative PAK transgenic mice. Neuron 42, 773–787.PubMedGoogle Scholar
  50. Humbert, S., Dhavan, R., and Tsai, L. (2000). p39 activates cdk5 in neurons, and is associated with the actin cytoskeleton. J Cell Sci 113, 975–983.PubMedGoogle Scholar
  51. Kandel, E. R. (2001). The molecular biology of memory storage: a dialogue between genes and synapses. Science 294, 1030–1038.PubMedGoogle Scholar
  52. Kaplan, M. S. (1988). Plasticity after brain lesions: contemporary concepts. Arch Phys Med Rehabil 69, 984–991.PubMedGoogle Scholar
  53. Kim, D., Nguyen, M. D., Dobbin, M. M., Fischer, A., Sananbenesi, F., Rodgers, J. T., Delalle, I., Baur, J. A., Sui, G., Armour, S. M., et al. (2007). SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis. EMBO J 26, 3169–3179.PubMedGoogle Scholar
  54. Kim, J. J., and Fanselow, M. S. (1992). Modality-specific retrograde amnesia of fear. Science 256, 675–677.Google Scholar
  55. Kim, Y., Sung, J. Y., Ceglia, I., Lee, K. W., Ahn, J. H., Halford, J. M., Kim, A. M., Kwak, S. P., Park, J. B., Ho Ryu, S., et al. (2006). Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology. Nature 442, 814–817.PubMedGoogle Scholar
  56. Klann, E., and Sweatt, J. D. (2007). Altered protein synthesis is a trigger for long-term memory formation. Neurobiol Learn Mem, 89,:247–259.PubMedGoogle Scholar
  57. Ko, J., Humbert, S., Bronson, R. T., Takahashi, S., Kulkarni, A. B., Li, E., and Tsai, L. H. (2001). p35 and p39 are essential for cyclin-dependent kinase 5 function during neurodevelopment. J Neurosci 21, 6758–6771.PubMedGoogle Scholar
  58. Krucker, T., Siggins, G. R., and Halpain, S. (2000). Dynamic actin filaments are required for stable long-term potentiation (LTP) in area CA1 of the hippocampus. Proc Natl Acad Sci U S A 97, 6856–6861.PubMedGoogle Scholar
  59. Kwon, Y. T., Gupta, A., Zhou, Y., Nikolic, M., and Tsai, L. H. (2000). Regulation of N-cadherin-mediated adhesion by the p35-Cdk5 kinase. Curr Biol 10, 363–372.PubMedGoogle Scholar
  60. Lee, M. S., Kao, S. C., Lemere, C. A., Xia, W., Tseng, H. C., Zhou, Y., Neve, R., Ahlijanian, M. K., and Tsai, L. H. (2003). APP processing is regulated by cytoplasmic phosphorylation. J Cell Biol 163, 83–95.PubMedGoogle Scholar
  61. Lee, M. S., Kwon, Y. T., Li, M., Peng, J., Friedlander, R. M., and Tsai, L. H. (2000). Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature 405, 360–364.PubMedGoogle Scholar
  62. Lee, S. Y., Voronov, S., Letinic, K., Nairn, A. C., Di Paolo, G., and De Camilli, P. (2005). Regulation of the interaction between PIPKI gamma and talin by proline-directed protein kinases. J Cell Biol 168, 789–799.PubMedGoogle Scholar
  63. Lee, S. Y., Wenk, M. R., Kim, Y., Nairn, A. C., and De Camilli, P. (2004). Regulation of synpatojanin 1 by cyclin-dependent kinase 5 at synapses. Proc Natl Acad Sci U S A 101, 546–551.PubMedGoogle Scholar
  64. Leuner, B., Falduto, J., and Shors, T. J. (2003). Associative memory formation increases the observation of dendritic spines in the hippocampus. J Neurosci 23, 659–665.PubMedGoogle Scholar
  65. Levenson, J. M., Roth, T. L., Lubin, F. D., Miller, C. A., Huang, I. C., Desai, P., Malone, L. M., and Sweatt, J. D. (2006). Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus. J Biol Chem 281, 15763–15773.PubMedGoogle Scholar
  66. Li, B. S., Sun, M. K., Zhang, L., Takahashi, S., Ma, W., Vinade, L., Kulkarni, A. B., Brady, R. O., and Pant, H. C. (2001). Regulation of NMDA receptors by cyclin-dependent kinase-5. Proc Natl Acad Sci U S A 98, 12742–12747.PubMedGoogle Scholar
  67. Lilja, L., Johansson, J. U., Gromada, J., Mandic, S. A., Fried, G., Berggren, P. O., and Bark, C. (2004). Cyclin-dependent kinase 5 associated with p39 promotes Munc18-1 phosphorylation and Ca(2+)-dependent exocytosis. J Biol Chem 279, 29534–29541.PubMedGoogle Scholar
  68. Lin, W., Dominguez, B., Yang, J., Aryal, P., Brandon, E. P., Gage, F. H., and Lee, K. F. (2005). Neurotransmitter acetylcholine negatively regulates neuromuscular synapse formation by a Cdk5-dependent mechanism. Neuron 46, 141–150.Google Scholar
  69. Lu, T., Pan, Y., Kao, S. Y., Li, C., Kohane, I., Chan, J., and Yankner, B. A. (2004). Gene regulation and DNA damage in the ageing human brain. Nature 429, 883–891.PubMedGoogle Scholar
  70. Malkani, S., and Rosen, J. B. (2000). Specific induction of early growth response gene 1 in the lateral nucleus of the amygdala following contextual fear conditioning in rats. Neuroscience 102, 853–861.Google Scholar
  71. Marder, E., and Goaillard, J. M. (2006). Variability, compensation and homeostasis in neuron and network function. Nat Rev Neurosci 7, 563–574.PubMedGoogle Scholar
  72. Matsubara, M., Kusubata, M., Ishiguro, K., Uchida, T., Titani, K., and Taniguchi, H. (1996). Site-specific phosphorylation of synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on physiological functions. J Biol Chem 271, 21108–21113.PubMedGoogle Scholar
  73. Matus, A. (2000). Actin-based plasticity in dendritic spines. Science 290, 754–758.PubMedGoogle Scholar
  74. Mesulam, M. M. (1999). Neuroplasticity failure in Alzheimer's disease: bridging the gap between plaques and tangles. Neuron 24, 521–529.PubMedGoogle Scholar
  75. Mitsios, N., Pennucci, R., Krupinski, J., Sanfeliu, C., Gaffney, J., Kumar, P., Kumar, S., Juan-Babot, O., and Slevin, M. (2007). Expression of cyclin-dependent kinase 5 mRNA and protein in the human brain following acute ischemic stroke. Brain Pathol 17, 11–23.PubMedGoogle Scholar
  76. Morabito, M. A., Sheng, M., and Tsai, L. H. (2004). Cyclin-dependent kinase 5 phosphorylates the N-terminal domain of the postsynaptic density protein PSD-95 in neurons. J Neurosci 24, 865–876.PubMedGoogle Scholar
  77. Murase, S., Mosser, E., and Schuman, E. M. (2002). Depolarization drives beta-Catenin into neuronal spines promoting changes in synaptic structure and function. Neuron 35, 91–105.PubMedGoogle Scholar
  78. Nakamura, S., Kawamoto, Y., Nakano, S., Akiguchi, I., and Kimura, J. (1997). p35nck5a and cyclin-dependent kinase 5 colocalize in Lewy bodies of brains with Parkinson's disease. Acta Neuropathol (Berl) 94, 153–157.Google Scholar
  79. Nguyen, C., and Bibb, J. A. (2003). Cdk5 and the mystery of synaptic vesicle endocytosis. J Cell Biol 163, 697–699.PubMedGoogle Scholar
  80. Nguyen, C., Hosokawa, T., Kuroiwa, M., Ip, N. Y., Nishi, A., Hisanaga, S., and Bibb, J. A. (2007). Differential regulation of the Cdk5-dependent phosphorylation sites of inhibitor-1 and DARPP-32 by depolarization. J Neurochem 103, 1582–1593.PubMedGoogle Scholar
  81. Nguyen, M. D., Lariviere, R. C., and Julien, J. P. (2001). Deregulation of Cdk5 in a mouse model of ALS: toxicity alleviated by perikaryal neurofilament inclusions. Neuron 30, 135–147.PubMedGoogle Scholar
  82. Nikolic, M., Chou, M. M., Lu, W., Mayer, B. J., and Tsai, L. H. (1998). The p35/Cdk5 kinase is a neuron-specific Rac effector that inhibits Pak1 activity. Nature 395, 194–198.PubMedGoogle Scholar
  83. Noble, W., Olm, V., Takata, K., Casey, E., Mary, O., Meyerson, J., Gaynor, K., LaFrancois, J., Wang, L., Kondo, T., et al. (2003). Cdk5 is a key factor in tau aggregation and tangle formation in vivo. Neuron 38, 555–565.PubMedGoogle Scholar
  84. Norrholm, S. D., Bibb, J. A., Nestler, E. J., Ouimet, C. C., Taylor, J. R., and Greengard, P. (2003). Cocaine-induced proliferation of dendritic spines in nucleus accumbens is dependent on the activity of cyclin-dependent kinase-5. Neuroscience 116, 19–22.PubMedGoogle Scholar
  85. Oakley, H., Cole, S. L., Logan, S., Maus, E., Shao, P., Craft, J., Guillozet-Bongaarts, A., Ohno, M., Disterhoft, J., Van Eldik, L., et al. (2006). ntraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J Neurosci 26, 10129–10140.PubMedGoogle Scholar
  86. Ohshima, T., Ogura, H., Tomizawa, K., Hayashi, K., Suzuki, H., Saito, T., kamei, H., Nishi, A., Bibb, J. A., Hisanaga, S., et al. (2005). Impairment of hippocampal long-term depression and defective spatial learning and memory in p35–/– mice. Journal of Neurochemistry 10, 4159–4168.Google Scholar
  87. Ohshima, T., Ward, J. M., Huh, C. G., Longenecker, G., Veeranna, Pant, H. C., Brady, R. O., Martin, L. J., and Kulkarni, A. B. (1996). Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death. Proc Natl Acad Sci U S A 93, 11173–11178.Google Scholar
  88. Otth, C., Concha, II, Arendt, T., Stieler, J., Schliebs, R., Gonzalez-Billault, C., and Maccioni, R. B. (2002). AbetaPP induces cdk5-dependent tau hyperphosphorylation in transgenic mice Tg2576. J Alzheimers Dis 4, 417–430.PubMedGoogle Scholar
  89. Patel, L. S., Wenzel, H. J., and Schwartzkroin, P. A. (2004). Physiological and morphological characterization of dentate granule cells in the p35 knock-out mouse hippocampus: evidence for an epileptic circuit. J Neurosci 24, 9005–9014.PubMedGoogle Scholar
  90. Patrick, G. N., Zhou, P., Kwon, Y. T., Howley, P. M., and Tsai, L. H. (1998). p35, the neuronal-specific activator of cyclin-dependent kinase 5 (Cdk5) is degraded by the ubiquitin-proteasome pathway. J Biol Chem 273, 24057–24064.PubMedGoogle Scholar
  91. Patrick, G. N., Zukerberg, L., Nikolic, M., de la Monte, S., Dikkes, P., and Tsai, L. H. (1999). Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402, 615–622.PubMedGoogle Scholar
  92. Patzke, H., Maddineni, U., Ayala, R., Morabito, M., Volker, J., Dikkes, P., Ahlijanian, M. K., and Tsai, L. H. (2003). Partial rescue of the p35-/- brain phenotype by low expression of a neuronal-specific enolase p25 transgene. J Neurosci 23, 2769–2778.PubMedGoogle Scholar
  93. Perez-Moreno, M., Jamora, C., and Fuchs, E. (2003). Sticky business: orchestrating cellular signals at adherens junctions. Cell 112, 535–548.PubMedGoogle Scholar
  94. Qu, D., Rashidian, J., Mount, M. P., Aleyasin, H., Parsanejad, M., Lira, A., Haque, E., Zhang, Y., Callaghan, S., Daigle, M., et al. (2007). Role of Cdk5-mediated phosphorylation of Prx2 in MPTP toxicity and Parkinson's disease. Neuron 55, 37–52.PubMedGoogle Scholar
  95. Rademakers, R., Sleegers, K., Theuns, J., Van den Broeck, M., Bel Kacem, S., Nilsson, L. G., Adolfsson, R., van Duijn, C. M., Van Broeckhoven, C., and Cruts, M. (2005). Association of cyclin-dependent kinase 5 and neuronal activators p35 and p39 complex in early-onset Alzheimer's disease. Neurobiol Aging 8, 1145–1151.Google Scholar
  96. Radulovic, J., Kammermeier, J., and Spiess, J. (1998). Relationship between fos production and classical fear conditioning: effects of novelty, latent inhibition, and unconditioned stimulus preexposure. J Neurosci 18, 7452–7461.PubMedGoogle Scholar
  97. Rashid, T., Banerjee, M., and Nikolic, M. (2001). Phosphorylation of Pak1 by the p35/Cdk5 kinase affects neuronal morphology. J Biol Chem 276, 49043–49052.PubMedGoogle Scholar
  98. Ris, L., Angelo, M., Plattner, F., Capron, B., Errington, M. L., Bliss, T. V., Godaux, E., and Giese, K. P. (2005). Sexual dimorphisms in the effect of low-level p25 expression on synaptic plasticity and memory. Eur J Neurosci 21, 3023–3033.PubMedGoogle Scholar
  99. Roberson, E. D., and Sweatt, J. D. (1999). A biochemical blueprint for long-term memory. Learn Mem 6, 399–416.Google Scholar
  100. Sananbenesi, F., Fischer, A., Wang, X., Schrick, C., Neve, R., Radulovic, J., and Tsai, L. H. (2007). A hippocampal Cdk5 pathway regulates extinction of contextual fear. Nat Neurosci 10, 1012–1019.PubMedGoogle Scholar
  101. Saura, C. A., Choi, S. Y., Beglopoulos, V., Malkani, S., Zhang, D., Shankaranarayana Rao, B. S., Chattarji, S., Kelleher, R. J., 3rd, Kandel, E. R., Duff, K., et al. (2004). Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron 42, 23–36.PubMedGoogle Scholar
  102. Scheff, S. (2003). Reactive synaptogenesis in aging and Alzheimer's disease: lessons learned in the Cotman laboratory. Neurochem Res 11, 1625–1630.Google Scholar
  103. Scheff, S. W., and Price, D. A. (2006). Alzheimer's disease-related alterations in synaptic density: neocortex and hippocampus. J Alzheimers Dis 9, 101–115.PubMedGoogle Scholar
  104. Schuman, E. M., and Murase, S. (2003). Adherins and synaptic plasticity: activity-dependent cyclin-dependent kinase 5 regulation of synaptic beta-catenin-cadherin interactions. Philos Trans R Soc Lond B Biol Sci 358, 749–756.PubMedGoogle Scholar
  105. Scoville, W. B., and Milner, B. (1957). Loss of recent memory after bilateral hippocampal lesions. Neuropsychiatry Clin Neurosci 2000 (classical article) 1, 103–113.Google Scholar
  106. Selcher, J. C., Weeber, E. J., Varga, A. W., Sweatt, J. D., and Swank, M. (2002). Protein kinase signal transduction cascades in mammalian associative conditioning. Neuroscientist 8, 122–131.PubMedGoogle Scholar
  107. Sen, A., Thom, M., Martinian, L., Jacobs, T., Nikolic, M., and Sisodiya, S. M. (2006). Deregulation of cdk5 in Hippocampal sclerosis. J Neuropathol Exp Neurol 65, 55–66.PubMedGoogle Scholar
  108. Sen, A., Thom, M., Martinian, L., Yogarajah, M., Nikolic, M., and Sisodiya, S. M. (2007). Increased immunoreactivity of cdk5 activators in hippocampal sclerosis. Neuroreport 18, 511–516.PubMedGoogle Scholar
  109. Shalizi, A., Gaudilliere, B., Yuan, Z., Stegmuller, J., Shirogane, T., Ge, Q., Tan, Y., Schulman, B., Harper, J. W., and Bonni, A. (2006). A calcium-regulated MEF2 sumoylation switch controls postsynaptic differentiation. Science 311, 1012–1017.PubMedGoogle Scholar
  110. Shimizu, K., Phan, T., Mansuy, I. M., and Storm, D. R. (2007). Proteolytic degradation of SCOP in the hippocampus contributes to activation of MAP kinase and memory. Cell 128, 1219–1229.PubMedGoogle Scholar
  111. Shuang, R., Zhang, L., Fletcher, A., Groblewski, G. E., Pevsner, J., and Stuenkel, E. L. (1998). Regulation of Munc-18/syntaxin 1A interaction by cyclin-dependent kinase 5 in nerve endings. J Biol Chem 273, 4957–4966.PubMedGoogle Scholar
  112. Silva, A. J., Paylor, R., Wehner, J. M., and Tonegawa, S. (1992). Impaired spatial learning in alpha-calcium-calmodulin kinase II mutant mice. Science 257, 206–211.PubMedGoogle Scholar
  113. Smith, P. D., Crocker, S. J., Jackson-Lewis, V., Jordan-Sciutto, K. L., Hayley, S., Mount, M. P., O'Hare, M. J., Callaghan, S., Slack, R. S., Przedborski, S., et al. (2004). Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson's disease. Proc Natl Acad Sci U S A 100, 13650–13655.Google Scholar
  114. Smith, P. D., Mount, M. P., Shree, R., Callaghan, S., Slack, R. S., Anisman, H., Vincent, I., Wang, X., Mao, Z., and Park, D. S. (2006). Calpain-regulated p35/cdk5 plays a central role in dopaminergic neuron death through modulation of the transcription factor myocyte enhancer factor 2. J Neurosci 26, 440–447.PubMedGoogle Scholar
  115. Soriano, S., Kang, D. E., Fu, M., Pestell, R., Chevallier, N., Zheng, H., and Koo, E. H. (2001). Presenilin 1 negatively regulates beta-catenin/T cell factor/lymphoid enhancer factor-1 signaling independently of beta-amyloid precursor protein and notch processing. J Cell Biol 152, 785–794.PubMedGoogle Scholar
  116. Spires, T. L., and Hannan, A. J. (2007). Molecular mechanisms mediating pathological plasticity in Huntington's disease and Alzheimer's disease. J Neurochem 100, 874–882.PubMedGoogle Scholar
  117. Swatton, J. E., Sellers, L. A., Faull, R. L., Holland, A., Iritani, S., and Bahn, S. (2004). Increased MAP kinase activity in Alzheimer's and Down syndrome but not in schizophrenia human brain. Eur J Neurosci 19, 2711–2719.PubMedGoogle Scholar
  118. Tan, T. C., Valova, V. A., Malladi, C. S., Graham, M. E., Berven, L. A., Jupp, O. J., Hansra, G., McClure, S. J., Sarcevic, B., Boadle, R. A., et al. (2003). Cdk5 is essential for synaptic vesicle endocytosis. Nat Cell Biol 5, 701–710.PubMedGoogle Scholar
  119. Tandon, A., Yu, H., Wang, L., Rogaeva, E., Sato, C., Chishti, M. A., Kawarai, T., Hasegawa, H., Chen, F., Davies, P., et al. (2003). Brain levels of CDK5 activator p25 are not increased in Alzheimer's or other neurodegenerative diseases with neurofibrillary tangles. J Neurochem 86, 572–583.PubMedGoogle Scholar
  120. Taniguchi, S., Fujita, Y., Hayashi, S., Kakita, A., Takahashi, H., Murayama, S., Saido, T. C., Hisanaga, S., Iwatsubo, T., and Hasegawa, M. (2001). Calpain-mediated degradation of p35 to p25 in postmortem human and rat brains. FEBS Lett 489, 46–50.PubMedGoogle Scholar
  121. Togashi, H., Abe, K., Mizoguchi, A., Takaoka, K., Chisaka, O., and Takeichi, M. (2002). Cadherin regulates dendritic spine morphogenesis. Neuron 35, 77–89.PubMedGoogle Scholar
  122. Tomizawa, K., Ohta, J., Matsushita, M., Moriwaki, A., Li, S. T., Takei, K., and Matsui, H. (2002). Cdk5/p35 regulates neurotransmitter release through phosphorylation and downregulation of P/Q-type voltage-dependent calcium channel activiy. J Neurosci 22, 2590–2597.PubMedGoogle Scholar
  123. Tomizawa, K., Sunada, S., Lu, Y. F., Oda, Y., Kinuta, M., Ohshima, T., Saito, T., Wei, F. Y., Matsushita, M., Li, S. T., et al. (2003). Cophosphorylation of amphiphysin I and dynamin I by Cdk5 regulates clathrin-mediated endocytosis of synaptic vesicles. J Cell Biol 163, 813–824.PubMedGoogle Scholar
  124. Toth, E., Bruin, J. P., Heinsbroek, R. P., and Joosten, R. N. (1996). Spatial learning and memory in calpastatin-deficient rats. Neurobiol Learn Mem 66, 230–235.PubMedGoogle Scholar
  125. Tsai, L. H., Lee, M. S., and Cruz, J. (2004). Cdk5, a therapeutic target for Alzheimer's disease? Biochim Biophys Acta 1697, 137–142.PubMedGoogle Scholar
  126. Tseng, H. C., Zhou, Y., Shen, Y., and Tsai, L. H. (2002). A survey of Cdk5 activator p35 and p25 levels in Alzheimer's disease brains. FEBS Lett 523, 58–62.PubMedGoogle Scholar
  127. Van den Haute, C., Spittaels, K., Van Dorpe, J., Lasrado, R., Vandezande, K., Laenen, I., Geerts, H., and Van Leuven, F. (2001). Coexpression of human cdk5 and its activator p35 with human protein tau in neurons in brain of triple transgenic mice. Neurobiol Dis 8, 32–44.PubMedGoogle Scholar
  128. Wang, J., Liu, S., Fu, Y., Wang, J. H., and Lu, Y. (2003). Cdk5 activation induces hippocampal CA1 cell death by directly phosphorylating NMDA receptors. Nat Neurosci 6, 1039–1047.PubMedGoogle Scholar
  129. Watase., K., and Zoghbi, H. Y. (2003). Modelling brain diseases in mice: the challenges of design and analysis. Nat Rev Genet 4, 296–307.PubMedGoogle Scholar
  130. Weishaupt, J. H., Kussmaul, L., Grotsch, P., Heckel, A., Rohde, G., Romig, H., Bahr, M., and Gillardon, F. (2003). Inhibition of CDK5 is protective in necrotic and apoptotic paradigms of neuronal cell death and prevents mitochondrial dysfunction. Mol Cell Neurosci 2, 489–502.Google Scholar
  131. Wu, P., Shen, Q., Dong, S., Xu, Z., Tsien, J. Z., and Hu, Y. (2007). Calorie restriction ameliorates neurodegenerative phenotypes in forebrain-specific presenilin-1 and presenilin-2 double knockout mice. Neurobiol Aging Epub ahead of print.Google Scholar
  132. Xie, Z., Samuels, B. A., and Tsai, L. H. (2006). Cyclin-dependent kinase 5 permits efficient cytoskeletal remodeling--a hypothesis on neuronal migration. Cereb Cortex 16, 64–68.Google Scholar
  133. Yan, Z., Chi, P., Bibb, J. A., Ryan, T. A., and Greengard, P. (2002). Roscovitine: a novel regulator of P/Q-type calcium channels and transmitter release in central neurons. J Physiol 540, 761–770.PubMedGoogle Scholar
  134. Yoo, B. C., and Lubec, G. (2001). p25 protein in neurodegeneration. Nature 411, 763–764; discussion 764–765.PubMedGoogle Scholar
  135. Zhang, M., Li, J., Chakrabarty, P., Bu, B., and Vincent, I. (2004). Cyclin-dependent kinase inhibitors attenuate protein hyperphosphorylation, cytoskeletal lesion formation, and motor defects in Niemann-Pick Type C mice. Am J Pathol 165, 843–853.PubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.European Neuroscience Institute (ENI), Department for Experimental NeuropathologyMedical School University GoettingenGermany

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