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Los antiinflamatorios no esteroideos pueden disminuir la actividad amiloidogénica de Abeta42 inhibiendo Rho
1Neuroscience Discovery Research and Bioresearch Technologies and Proteins, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. zhou_yan_yz@lilly.com
Science (New York, N.Y.)
|November 15, 2003
Resumen
Algunos medicamentos antiinflamatorios no esteroideos (AINE) reducen el amiloide-beta 42 (Abeta42) al inhibir la vía de la quinasa asociada a Rho (ROCK). Esta vía regula el procesamiento de la proteína precursora amiloide, ofreciendo un nuevo objetivo terapéutico para la enfermedad de Alzheimer.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- La neurociencia es la neurociencia.
- Farmacología Farmacología.
Sus antecedentes:
- Amyloid-beta 42 (Abeta42) es un péptido clave en la patogénesis de la enfermedad de Alzheimer.
- Ciertos medicamentos antiinflamatorios no esteroideos (AINE) han demostrado una capacidad para reducir la secreción de Abeta42.
- Los mecanismos moleculares precisos que subyacen a este efecto de los AINE aún no se comprenden por completo.
Objetivo del estudio:
- Investigar el papel de la vía de la kinasa asociada a Rho (ROCK) en la regulación de la producción de Abeta42.
- Para determinar si los AINE que inhiben Abeta42 lo hacen a través de la inhibición de la vía ROCK.
- Evaluar el potencial terapéutico de la inhibición de ROCK para reducir los niveles cerebrales de Abeta42 en un modelo de enfermedad de Alzheimer.
Principales métodos:
- Pruebas in vitro para medir la secreción de Abeta42.
- La inhibición de Rho y de la quinasa asociada a Rho (ROCK) mediante el uso de inhibidores específicos.
- Administración de un inhibidor selectivo de ROCK (Y-27632) a un modelo de ratón transgénico de la enfermedad de Alzheimer.
- Cuantificación de los niveles cerebrales de Abeta42 en ratones tratados.
Principales resultados:
- Se encontró que Rho y ROCK regulan preferentemente la producción de Abeta42 in vitro.
- Solo los AINE que exhibieron actividad inhibidora de Rho fueron efectivos para reducir Abeta42.
- La inhibición selectiva de ROCK con Y-27632 redujo significativamente los niveles cerebrales de Abeta42 en un modelo de ratón transgénico de Alzheimer.
Conclusiones:
- La vía Rho-ROCK está implicada en la regulación del procesamiento de proteínas precursoras de amiloide y la generación de Abeta42.
- Un subconjunto de AINE puede reducir Abeta42 inhibiendo la actividad de Rho.
- Dirigirse a la vía Rho-ROCK representa una estrategia terapéutica potencial para reducir Abeta42 en la enfermedad de Alzheimer.
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