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

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Abstract

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.

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Acknowledgments

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.

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  1. European Neuroscience Institute (ENI), Department for Experimental Neuropathology, Medical School University Goettingen, Max Planck Society, Germany

    Andre Fischer

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  1. Andre Fischer
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  2. Li-Huei Tsai
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Correspondence to Andre Fischer .

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  1. Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China

    Nancy Y. Ip

  2. Department of Brain and Cognitive Science, Howard Hughes Medical Institute, Massachusetts Institute of Technology, 77 Massachusetts Avenue, 02139, Cambridge, MA, USA

    Li-Huei Tsai

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Fischer, A., Tsai, LH. (2008). Cyclin-Dependent Kinase 5 (Cdk5): Linking Synaptic Plasticity and Neurodegeneration. In: Ip, N.Y., Tsai, LH. (eds) Cyclin Dependent Kinase 5 (Cdk5). Springer, Boston, MA. https://doi.org/10.1007/978-0-387-78887-6_17

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