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La activación de la caspasa precede y conduce a los enredos
Alix de Calignon1, Leora M Fox, Rose Pitstick
1MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Alzheimer's Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Nature
|April 2, 2010
Resumen
La activación de la caspasa, no los enredos neurofibrilares (NFT), inicia la patología de la tau en los modelos de la enfermedad de Alzheimer. Este hallazgo sugiere que las especies de tau solubles, no los enredos, impulsan la neurodegeneración, ofreciendo nuevos objetivos terapéuticos.
Área de la Ciencia:
- La neurociencia es la neurociencia.
- Biología Molecular Biología Molecular
- Patología Patología Patología.
Sus antecedentes:
- Los estudios post-mortem relacionan los enredos neurofibrilares (NFT) con la muerte neuronal en la enfermedad de Alzheimer (EA) y la demencia frontotemporal.
- Los NFT están asociados con la activación de la caspasa y la apoptosis, lo que sugiere que los enredos causan neurodegeneración.
Objetivo del estudio:
- Para investigar la relación temporal entre la activación de la caspasa y la formación de NFT in vivo.
- Aclarar el papel de la tau dividida por caspasa en el inicio de la patología tau y la neurodegeneración.
Principales métodos:
- Imágenes multifotónicas in vivo en ratones vivos transgénicos tau (tendencia TG4510).
- Observación de la activación de la caspase y la formación de NFT.
- Introducción de las estructuras tau de tipo silvestre de 4 repeticiones (tau-4R) y las estructuras tau de caspases en ratones de tipo silvestre.
Principales resultados:
- La activación de Caspase precede la formación de NFT por horas o días.
- Los nuevos NFT se forman en un día, y las neuronas sobreviven con la actividad caspase suprimida.
- La activación de la caspasa, el truncamiento de la tau y la agregación se desencadenaron por la introducción de tau-4R.
- Agregados inducidos miméticos de tau escindidos por caspase, epítopos enredados y reclutamiento de tau endógeno.
Conclusiones:
- Un nuevo modelo propone que la activación de la caspasa inicia la escisión de la tau, lo que lleva a la formación de NFT.
- Los NFT pueden estar "fuera de la vía" para la muerte neuronal aguda, con las neuronas que llevan enredos siendo de larga duración.
- Es probable que las especies de tau solubles, en lugar de la tau fibrilar, sean los principales agentes tóxicos en la neurodegeneración.
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