Spatial Learning Impairment, Enhanced CDK5/p35 Activity, and Downregulation of NMDA Receptor Expression in Transgenic Mice Expressing Tau-Tubulin Kinase 1
Open Access
- 31 December 2008
- journal article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 28 (53), 14511-14521
- https://doi.org/10.1523/jneurosci.3417-08.2008
Abstract
Tau-tubulin kinase-1 (TTBK1) is involved in phosphorylation of tau protein at specific Serine/Threonine residues found in paired helical filaments, suggesting its role in tauopathy pathogenesis. We found that TTBK1 levels were upregulated in brains of human Alzheimer' disease (AD) patients compared with age-matched non-AD controls. To understand the effects of TTBK1 activationin vivo, we developed transgenic mice harboring human full-length TTBK1 genomic DNA (TTBK1-Tg). Transgenic TTBK1 is highly expressed in subiculum and cortical pyramidal layers, and induces phosphorylated neurofilament aggregation. TTBK1-Tg mice show significant age-dependent memory impairment as determined by radial arm water maze test, which is associated with enhancement of tau and neurofilament phosphorylation, increased levels of p25 and p35, both activators of cyclin-dependent protein kinase 5 (CDK5), enhanced calpain I activity, and reduced levels of hippocampal NMDA receptor types 2B (NR2B) and D. Enhanced CDK5/p35 complex formation is strongly correlated with dissociation of F-actin from p35, suggesting the inhibitory mechanism of CDK5/p35 complex formation by F-actin. Expression of recombinant TTBK1 in primary mouse cortical neurons significantly downregulated NR2B in a CDK5- and calpain-dependent manner. These data suggest that TTBK1 in AD brain may be one of the underlying mechanisms inducing CDK5 and calpain activation, NR2B downregulation, and subsequent memory dysfunction.Keywords
This publication has 68 references indexed in Scilit:
- WAVE1 controls neuronal activity-induced mitochondrial distribution in dendritic spinesProceedings of the National Academy of Sciences, 2008
- Neurabin-I Is Phosphorylated by Cdk5: Implications for Neuronal Morphogenesis and Cortical MigrationMolecular Biology of the Cell, 2007
- Fyn-mediated Phosphorylation of NR2B Tyr-1336 Controls Calpain-mediated NR2B Cleavage in Neurons and Heterologous SystemsJournal of Biological Chemistry, 2007
- CpG Island Mapping by Epigenome PredictionPLoS Computational Biology, 2007
- Epitope mapping of mAbs AT8 and Tau5 directed against hyperphosphorylated regions of the human tau proteinBiochemical and Biophysical Research Communications, 2007
- Interferon-γ and Tumor Necrosis Factor-α Regulate Amyloid-β Plaque Deposition and β-Secretase Expression in Swedish Mutant APP Transgenic MiceThe American Journal of Pathology, 2007
- Cdk5 phosphorylates and stabilizes p27kip1 contributing to actin organization and cortical neuronal migrationNature, 2005
- Opposing Roles of Transient and Prolonged Expression of p25 in Synaptic Plasticity and Hippocampus-Dependent MemoryNeuron, 2005
- The Role of Mitogen-Activated Protein Kinase Pathways in Alzheimer’s DiseaseNeurosignals, 2002
- Axonopathy, tau abnormalities, and dyskinesia, but no neurofibrillary tangles in p25‐transgenic miceJournal of Comparative Neurology, 2002