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Quantitative Measurement of γ-Secretase-mediated Amyloid Precursor Protein and Notch Cleavage in Cell-based Luciferase Reporter Assay Platforms
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Published on: January 25, 2018

Moduladores de gamma secretasa dirigidos al sustrato.

Thomas L Kukar1, Thomas B Ladd, Maralyssa A Bann

  • 1Department of Neuroscience, Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA. kukar.thomas@mayo.edu

Nature
|June 13, 2008
PubMed
Resumen
Este resumen es generado por máquina.

Los moduladores de gamma secretasa de moléculas pequeñas (GSM) se dirigen a la proteína precursora amiloide (APP) y al beta amiloide, no al complejo gamma secretasa en sí mismo. Esta doble acción puede ofrecer un enfoque sinérgico para la terapia de la enfermedad de Alzheimer.

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Área de la Ciencia:

  • La neurociencia es la neurociencia.
  • La bioquímica es la bioquímica.
  • Farmacología Farmacología.

Sus antecedentes:

  • La terapia de la enfermedad de Alzheimer (EA) tiene como objetivo reducir el amiloide-beta 42 (Abeta42) utilizando moduladores de gamma-secretasa (GSM).
  • El objetivo molecular preciso de las GSMs dentro de la vía de la gamma-secretasa sigue siendo incompletamente entendido.
  • La identificación de objetivos GSM es crucial para el desarrollo de terapias efectivas de AD.

Objetivo del estudio:

  • Identificar las dianas moleculares directas de los moduladores de pequeñas moléculas de gamma secretasa (GSM).
  • Para aclarar el mecanismo por el cual los GSM modulan la producción de Abeta42 y la agregación de beta amiloide.
  • Para explorar el potencial terapéutico de GSMs de orientación de sustrato para la enfermedad de Alzheimer.

Principales métodos:

  • Desarrollo y aplicación de GSMs fotoactivados biotinilados (photoprobes).
  • Los ensayos de etiquetado de afinidad en células H4 de neuroglioma humano para identificar objetivos de proteínas.
  • Ensayos de competencia con varios GSM y experimentos de etiquetado específicos del sustrato.
  • Mutagénesis dirigida al sitio del sitio de unión de la proteína precursora amiloide (APP).

Principales resultados:

  • Las fotosondas GSM etiquetaron la proteína precursora amiloide (APP), sus fragmentos carboxiterminales y el péptido beta amiloide, pero no los componentes centrales de la gamma secretasa.
  • La interacción GSM se localizó en los residuos 28-36 de beta amiloide, una región crítica para la agregación.
  • Las GSM alteraron la producción de oligómeros de beta amiloide derivados de las células, y las mutaciones de APP afectaron la sensibilidad GSM.
  • El etiquetado del sustrato por GSMs fue más eficiente para APP que para Notch.

Conclusiones:

  • Las GSM actúan dirigiéndose directamente al sustrato de la APP, no al complejo enzimático gamma-secretasa.
  • Este mecanismo de orientación al sustrato vincula la modulación de la producción de Abeta42 con la inhibición de la agregación beta-amiloide.
  • Esta acción dual ofrece una estrategia terapéutica potencialmente sinérgica para la enfermedad de Alzheimer, ampliando el concepto de objetivos farmacológicos.