Spatial learning impairment, enhanced CDK5/p35 activity, and downregulation of NMDA receptor expression in transgenic mice expressing tau-tubulin kinase 1.

Sato, Shinji; Xu, Jiqing; Okuyama, Satoshi; Martinez, Lindsey B; Walsh, Shannon M; Jacobsen, Michael T; Swan, Russell J; Schlautman, Joshua D; Ciborowski, Pawel; Ikezu, Tsuneya

Sato, Shinji; Xu, Jiqing; Okuyama, Satoshi; Martinez, Lindsey B; Walsh, Shannon M; Jacobsen, Michael T; Swan, Russell J; Schlautman, Joshua D; Ciborowski, Pawel; Ikezu, Tsuneya.

Afiliación

Sato S; Department of Pharmacology and Experimental Neuroscience and Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska 68198-5880, USA.

J Neurosci ; 28(53): 14511-21, 2008 Dec 31.

Article en En | MEDLINE | ID: mdl-19118186

RESUMEN

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.

Asunto(s)

Regulación hacia Abajo/genética; Discapacidades para el Aprendizaje/genética; Proteínas del Tejido Nervioso/metabolismo; Proteínas Serina-Treonina Quinasas/genética; Receptores de N-Metil-D-Aspartato/metabolismo; Actinas/metabolismo; Factores de Edad; Enfermedad de Alzheimer/patología; Animales; Calpaína/metabolismo; Células Cultivadas; Corteza Cerebral/citología; Corteza Cerebral/patología; Hipocampo/metabolismo; Humanos; Espectrometría de Masas; Aprendizaje por Laberinto/fisiología; Ratones; Ratones Transgénicos; Proteínas Asociadas a Microtúbulos/genética; Proteínas Asociadas a Microtúbulos/metabolismo; Peso Molecular; Proteínas del Tejido Nervioso/genética; Neuronas/metabolismo; Proteínas Nucleares/genética; Proteínas Nucleares/metabolismo; ARN Interferente Pequeño/genética; ARN Interferente Pequeño/metabolismo; Receptores de N-Metil-D-Aspartato/genética; Conducta Espacial/fisiología; Transfección; Regulación hacia Arriba; Región del Complejo T del Genoma

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Regulación hacia Abajo / Proteínas Serina-Treonina Quinasas / Receptores de N-Metil-D-Aspartato / Discapacidades para el Aprendizaje / Proteínas del Tejido Nervioso Límite: Animals / Humans Idioma: En Revista: J Neurosci Año: 2008 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

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