ROCK inhibition prevents tau hyperphosphorylation and p25/CDK5 increase after global cerebral ischemia.

Castro-Alvarez, John Fredy; Gutiérrez‐Vargas, Johanna; Darnaudéry, Muriel; Cardona‐Gómez, Gloria Patricia

doi:10.1037/a0023167

Cited by 41 publications

(40 citation statements)

References 64 publications

(112 reference statements)

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“…The improvement in the 3xTg-AD mice both in terms of their Tau pathology and their behavior, reinforces and extends several reports on the beneficial effects of clearing hyperphosphorylated Tau (Alvarez et al, 1999; Zheng et al, 2002, 2005, 2010; Wang et al, 2003; Zhang et al, 2004, 2013; Wen et al, 2007; Piedrahita et al, 2010; Castro-Alvarez et al, 2011; Crews et al, 2011). Also, a great deal of evidence supports the occurrence of behavioral deficits in 3xTg-AD mice (Oddo et al, 2003; Billings et al, 2005; Clinton et al, 2007; Gulinello et al, 2009).…”

Section: Discussionsupporting

confidence: 87%

Long- and short-term CDK5 knockdown prevents spatial memory dysfunction and tau pathology of triple transgenic Alzheimerâ€™s mice

Castro-Alvarez

Uribe-Arias

Kosik

et al. 2014

Front. Aging Neurosci.

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CDK5 is a member of the cyclin-dependent kinase family with diverse functions in both the developing and mature nervous system. The inappropriate activation of CDK5 due to the proteolytic release of the activator fragment p25 from the membrane contributes to the formation of neurofibrillary tangles and chronic neurodegeneration. At 18 months of age 3xTg-AD mice were sacrificed after 1 year (long term) or 3 weeks (short term) of CDK5 knockdown. In long-term animals CDK5 knockdown prevented insoluble Tau formation in the hippocampi and prevented spatial memory impairment. In short-term animals, CDK5 knockdown showed reduction of CDK5, reversed Tau aggregation, and improved spatial memory compared to scrambled treated old 3xTg-AD mice. Neither long-term nor short-term CDK5 knock-down had an effect on old littermates. These findings further validate CDK5 as a target for Alzheimer’s disease both as a preventive measure and after the onset of symptoms.

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Section: Discussionsupporting

confidence: 87%

Long- and short-term CDK5 knockdown prevents spatial memory dysfunction and tau pathology of triple transgenic Alzheimerâ€™s mice

Castro-Alvarez

Uribe-Arias

Kosik

et al. 2014

Front. Aging Neurosci.

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“…Inhibition of RhoA activity also reduces cerebral infarction in focal ischemia models (Kilic et al, 2010; Koumura et al, 2011; Yamashita et al, 2007), and prevents tau hyperphosphorylation and p25/CDK5 increase after global cerebral ischemia (Castro-Alvarez et al, 2011). The present study provides new information about upregulation of the GEF-H1 activity, a key upstream regulator of the RhoA activity after brain ischemia.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of the GEF-H1 pathway after transient cerebral ischemia

Luo

Roman

Liu

et al. 2015

Experimental Neurology

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The microtubule-dependent GEF-H1 pathway controls synaptic re-networking and overall gene expression via regulating cytoskeleton dynamics. Understanding this pathway after ischemia is essential to developing new therapies for neuronal function recovery. However, how the GEF-H1 pathway is regulated following transient cerebral ischemia remains unknown. This study employed a rat model of transient forebrain ischemia to investigate alterations of the GEF-H1 pathway using Western blotting, confocal and electron microscopy, dephosphorylation analysis, and pull-down assay. The GEF-H1 activity was significantly upregulated by: (i) dephosphorylation and (ii) translocation to synaptic membrane and nuclear structures during the early phase of reperfusion. GEF-H1 protein was then downregulated in the brain regions where neurons were destined to undergo delayed neuronal death, but markedly upregulated in neurons that were resistant to the same episode of cerebral ischemia. Consistently, GTP-RhoA, a GEF-H1 substrate, was significantly upregulated after brain ischemia. Electron microscopy further showed that neuronal microtubules were persistently depolymerized in the brain region where GEF-H1 protein was downregulated after brain ischemia. The results demonstrate that the GEF-H1 activity is significantly upregulated in both vulnerable and resistant brain regions in the early phase of reperfusion. However, GEF-H1 protein is downregulated in the vulnerable neurons but upregulated in the ischemic resistant neurons during the recovery phase after ischemia. The initial upregulation of GEF-H1 activity may contribute to excitotoxicity, whereas the late upregulation of GEF-H1 protein may promote neuroplasticity after brain ischemia.

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“…Sin embargo, son aún inciertos el o los mecanismos de la lesión post-isquémica en el hipocampo y si ellos se relacionan con el deterioro cognitivo. Algunos estudios, incluidos los nuestros (Castro-Alvarez, et al, 2011, 2014a, han demostrado que la hiperfosforilación de Tau es considerada un marcador de neurodegeneración posterior a la isquemia cerebral y está estrechamente correlacionado con el desorden cognitivo y la demencia (Pluta, et al, 2011) Hasta el momento no hay ningún tratamiento eficaz para tratar el deterioro cognitivo post-isquemia. Algunos de los fármacos usados para el tratamiento de la demencia en la enfermedad de Alzheimer (AD), han demostrado algunos efectos positivos en la discapacidad cognitiva postisquemia (Brainin, et al, 2015).…”

Section: Figura 1 El Infarto Generado Tras Una Isquemia Focalunclassified

Terapia génica en enfermedades neurodegenerativas y demencia post infarto cerebral: perspectiva de traslación

Gutiérrez‐Vargas

Cardona‐Gómez

2017

Rev. Acad. Colomb. Cienc. Ex. Fis. Nat.

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Artículo de posesión para el ingreso como miembro correspondiente a la Academia Colombiana de Ciencias Exactas, Físicas y Naturales el 24 de noviembre de 2016 ResumenLas enfermedades cerebrovasculares se han convertido en un problema de salud mundial debido a su alta tasa de mortalidad y discapacidad. En Colombia constituyen la tercera causa de riesgo de muerte y en el mundo son la primera causa de discapacidad física y mental. Se han evaluado muchas estrategias terapéuticas en modelos experimentales y en ensayos clínicos sin buenos resultados. Algunas de las falencias de los estudios sobre tales estrategias terapéuticas son el reducido tiempo de intervención (menos de cuatro horas y media), así como el poco tiempo de protección y la falta de seguimiento de la terapia, lo cual genera secuelas a largo plazo en los pacientes. La terapia génica ha demostrado ser una herramienta de gran utilidad para el tratamiento de las enfermedades neurodegenerativas; sin embargo, en el caso específico de la isquemia cerebral hay pocos estudios experimentales. En nuestras investigaciones hemos constatado el potencial de la terapia génica basada en el ARN de interferencia para prevenir y revertir la neurodegeneración y el deterioro cognitivo después de un infarto cerebral, aunque todavía deben sortearse algunas dificultades terapéuticas inherentes al sistema nervioso cerebral, así como concertar los intereses de los diversos sectores involucrados: el Gobierno, las empresas y el sector científico y académico, con el fin de incentivar la inversión y facilitar la aplicación en otras partes del país de las terapias promisorias propuestas en nuestra región para disminuir las secuelas de enfermedades crónicas no transmisibles, entre ellas la incapacidad física y mental después de un infarto cerebral. © 2017. Acad. Colomb. Cienc. Ex. Fis. Nat. Palabras claves:Infarto cerebral; Enfermedades neurodegenerativas; Demencia; Terapia génica; ARN de Interferencia; Medicina de traslación. Gene therapy in neurodegeneration and dementia post-stroke AbstractCerebrovascular disease has become a worldwide health problem due to its high mortality and disability rate. It is the third leading cause of death risk in our country and the first cause of physical and mental disability in the world. Many therapeutic strategies have been evaluated both in experimental models and in clinical trials without success. One of the major shortcomings of these therapeutic studies is the limitation in the intervention time (less than four and a half hours) and the short time of protection or follow-up of the therapy, which generates long-term sequelae in the patients. Gene therapy has been shown to be a very useful tool for the treatment of neurodegenerative diseases; however, experimental studies are few, specifically in cerebral ischemia. Our research has demonstrated the potential benefit of RNA interference based gene therapy to prevent and reverse neurodegenerative effects and cognitive impairment following a stroke. However, therapeutic difficulties inherent to th...

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ROCK inhibition prevents tau hyperphosphorylation and p25/CDK5 increase after global cerebral ischemia.

Cited by 41 publications

References 64 publications

Long- and short-term CDK5 knockdown prevents spatial memory dysfunction and tau pathology of triple transgenic Alzheimerâ€™s mice

Long- and short-term CDK5 knockdown prevents spatial memory dysfunction and tau pathology of triple transgenic Alzheimerâ€™s mice

Upregulation of the GEF-H1 pathway after transient cerebral ischemia

Terapia génica en enfermedades neurodegenerativas y demencia post infarto cerebral: perspectiva de traslación

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