PMID- 19118186
OWN - NLM
STAT- MEDLINE
DCOM- 20090409
LR  - 20211203
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 28
IP  - 53
DP  - 2008 Dec 31
TI  - Spatial learning impairment, enhanced CDK5/p35 activity, and downregulation of 
      NMDA receptor expression in transgenic mice expressing tau-tubulin kinase 1.
PG  - 14511-21
LID - 10.1523/JNEUROSCI.3417-08.2008 [doi]
AB  - 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 activation in 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.
FAU - Sato, Shinji
AU  - Sato S
AD  - Department of Pharmacology and Experimental Neuroscience and Center for 
      Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical 
      Center, Omaha, Nebraska 68198-5880, USA.
FAU - Xu, Jiqing
AU  - Xu J
FAU - Okuyama, Satoshi
AU  - Okuyama S
FAU - Martinez, Lindsey B
AU  - Martinez LB
FAU - Walsh, Shannon M
AU  - Walsh SM
FAU - Jacobsen, Michael T
AU  - Jacobsen MT
FAU - Swan, Russell J
AU  - Swan RJ
FAU - Schlautman, Joshua D
AU  - Schlautman JD
FAU - Ciborowski, Pawel
AU  - Ciborowski P
FAU - Ikezu, Tsuneya
AU  - Ikezu T
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Actins)
RN  - 0 (Microtubule-Associated Proteins)
RN  - 0 (NR2B NMDA receptor)
RN  - 0 (NR2D NMDA receptor)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 0 (neuronal Cdk5 activator (p25-p35))
RN  - EC 2.7.1.11 (tau-tubulin kinase)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 3.4.22.- (Calpain)
RN  - EC 3.4.22.52 (Capn1 protein, mouse)
SB  - IM
MH  - Actins/metabolism
MH  - Age Factors
MH  - Alzheimer Disease/pathology
MH  - Animals
MH  - Calpain/metabolism
MH  - Cells, Cultured
MH  - Cerebral Cortex/cytology/pathology
MH  - Down-Regulation/*genetics
MH  - Hippocampus/metabolism
MH  - Humans
MH  - Learning Disabilities/*genetics
MH  - Mass Spectrometry
MH  - Maze Learning/physiology
MH  - Mice
MH  - Mice, Transgenic
MH  - Microtubule-Associated Proteins/genetics/metabolism
MH  - Molecular Weight
MH  - Nerve Tissue Proteins/genetics/*metabolism
MH  - Neurons/metabolism
MH  - Nuclear Proteins/genetics/metabolism
MH  - Protein Serine-Threonine Kinases/*genetics
MH  - RNA, Small Interfering/genetics/metabolism
MH  - Receptors, N-Methyl-D-Aspartate/genetics/*metabolism
MH  - Spatial Behavior/physiology
MH  - Transfection
MH  - Up-Regulation
MH  - t-Complex Genome Region
PMC - PMC6671237
EDAT- 2009/01/02 09:00
MHDA- 2009/04/10 09:00
PMCR- 2009/06/30
CRDT- 2009/01/02 09:00
PHST- 2009/01/02 09:00 [entrez]
PHST- 2009/01/02 09:00 [pubmed]
PHST- 2009/04/10 09:00 [medline]
PHST- 2009/06/30 00:00 [pmc-release]
AID - 28/53/14511 [pii]
AID - 10.1523/JNEUROSCI.3417-08.2008 [doi]
PST - ppublish
SO  - J Neurosci. 2008 Dec 31;28(53):14511-21. doi: 10.1523/JNEUROSCI.3417-08.2008.