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La proteína activadora de la gamma secretasa es un objetivo terapéutico para la enfermedad de Alzheimer

Gen He¹, Wenjie Luo, Peng Li

¹Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA.

|September 3, 2010

Resumen

Una nueva proteína, la proteína activadora de la gamma secretasa (GSAP), aumenta selectivamente la producción de beta amiloide en la enfermedad de Alzheimer. Dirigirse al GSAP ofrece una estrategia terapéutica para reducir el beta-amiloide sin dañar las funciones celulares esenciales.

Área de la Ciencia:

La neurociencia es la neurociencia.
Biología Molecular Biología Molecular
La bioquímica es la bioquímica.

Sus antecedentes:

La acumulación de beta amiloide es una característica clave de la enfermedad de Alzheimer.
La actividad de la gamma-secretasa produce beta-amiloide, pero su especificidad de sustrato es poco conocida.
La inhibición selectiva de la gamma-secretasa es crucial para evitar efectos secundarios en sustratos esenciales como Notch.

Objetivo del estudio:

Para identificar nuevos reguladores de la actividad de la gamma-secretasa.
Para dilucidar los mecanismos de la especificidad del sustrato de la gamma-secretasa.
Explorar nuevos objetivos terapéuticos para reducir la producción de beta amiloide.

Principales métodos:

Descubrimiento y caracterización de una nueva proteína activadora de la gamma secretasa (GSAP).
Ensayos in vitro utilizando GSAP recombinante para medir la producción de beta amiloide.
Ensayos basados en células y estudios in vivo en un modelo de ratón para evaluar el papel de GSAP en la amiloide-beta y la formación de placa.
Investigación del mecanismo de acción de imatinib en las interacciones GSAP-sustrato.

Principales resultados:

GSAP fue identificado como una proteína que aumenta selectivamente la producción de beta amiloide mediante la interacción con la gamma-secretasa y APP-CTF.
GSAP no afecta la hendidura de la muesca, lo que indica la especificidad del sustrato.
La reducción de los niveles de GSAP disminuyó la producción de beta amiloide in vitro e in vivo.
El imatinib inhibe la beta amiloide al prevenir la interacción del GSAP con el APP-CTF.

Conclusiones:

GSAP es un nuevo regulador que confiere especificidad de sustrato a la gamma-secretasa.
GSAP representa un objetivo terapéutico prometedor para la enfermedad de Alzheimer, permitiendo la reducción de beta amiloide sin afectar la señalización de Notch.
El efecto terapéutico de imatinib está mediado a través de su inhibición de la interacción GSAP-APP-CTF.

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