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La proteína precursora de amiloide-β secretada funciona como un ligando GABAB para modular la transmisión sináptica
Heather C Rice1,2, Daniel de Malmazet3,4, An Schreurs5
1VIB Center for Brain & Disease Research, Leuven, Belgium.
Science (New York, N.Y.)
|January 12, 2019
Resumen
Los investigadores identificaron un receptor para la proteína precursora de amiloide-β secretada (sAPP) en el GABABR1a. Esta interacción regula la transmisión sináptica y la actividad neuronal, ofreciendo nuevos conocimientos sobre la enfermedad de Alzheimer.
Área de la Ciencia:
- La neurociencia
- Biología molecular
- Biología celular
Sus antecedentes:
- La proteína precursora de amiloide-β (APP) es crucial en la patogénesis de la enfermedad de Alzheimer.
- El papel fisiológico preciso de APP, particularmente su forma secretada (sAPP), en las sinapsis no se comprende completamente.
- Se ha planteado la hipótesis de un receptor sináptico para sAPP, pero no se ha identificado.
Objetivo del estudio:
- Para identificar el receptor sináptico para la APP secretada (sAPP).
- Para aclarar la función fisiológica de la sAPP en la transmisión sináptica.
- Investigar el papel de la interacción sAPP-receptor en la regulación de la actividad neuronal.
Principales métodos:
- Se investigó la interacción de unión entre el dominio de extensión de la sAPP y la subunidad 1a del receptor de ácido γ-aminobutírico tipo B (GABABR1a).
- Se evaluaron los efectos de la unión de sAPP-GABABR1a en la transmisión sináptica y la facilitación en las sinapsis del hipocampo del ratón.
- Utilizó un péptido correspondiente a la región de unión GABABR1a de APP para estudiar su efecto en la actividad neuronal in vivo.
Principales resultados:
- Se ha demostrado una unión directa entre el dominio de extensión de sAPP y el dominio sushi 1 de GABABR1a.
- Se demostró que la unión de sAPP-GABABR1a inhibe la liberación de las vesículas sinápticas, suprimiendo la transmisión sináptica y mejorando la facilitación a corto plazo.
- Se confirmó que un péptido derivado de la APP que apunta al GABABR1a suprime la actividad neuronal del hipocampo in vivo.
Conclusiones:
- Se identificó el GABABR1a como un receptor sináptico funcional para la sAPP.
- Reveló un nuevo papel fisiológico para la sAPP en la modulación de la actividad GABABR1a.
- Se estableció que la sAPP regula la transmisión sináptica a través de GABABR1a, proporcionando objetivos terapéuticos potenciales para la enfermedad de Alzheimer.
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