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Evolución estructural de las fibrillas β-amiloides mutantes de Iowa de estados polimórficos a estados homogéneos bajo
Wei Qiang1, Wai-Ming Yau, Robert Tycko
1Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0520, United States.
Journal of the American Chemical Society
|March 2, 2011
Resumen
Las variaciones estructurales en las fibrillas de la enfermedad de Alzheimer (EA) se pueden seleccionar utilizando un protocolo de siembra repetida. Este método aísla una sola estructura de fibrillas, revelando sensibilidad a las condiciones de crecimiento y implicaciones para la investigación de fibrillas amiloides.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Estructural Biología estructural.
- La neurociencia es la neurociencia.
Sus antecedentes:
- El polimorfismo estructural en las fibrillas β-amiloide (Aβ) está relacionado con la patogénesis de la enfermedad de Alzheimer (EA).
- Comprender la estructura de las fibrillas es crucial para desarrollar terapias efectivas para la EA.
- El mutante D23N-Aβ1-40, asociado con la enfermedad de Alzheimer familiar, exhibe polimorfismo de las fibrillas.
Objetivo del estudio:
- Desarrollar y validar un protocolo de siembra repetida para la selección de estructuras de fibrillas Aβ homogéneas.
- Investigar la evolución estructural y la estabilidad de las fibrillas D23N-Aβ{1-40) en condiciones controladas.
- Evaluar el impacto de las variaciones estructurales en la fluorescencia de la tioflavina T (ThT).
Principales métodos:
- Protocolo de siembra repetido para la amplificación de las fibrillas.
- Espectroscopia de fluorescencia de la tioflavina T (ThT). espectroscopia de fluorescencia de la tioflavina T (ThT). espectroscopia de fluorescencia de la tioflavina T (ThT). espectroscopia de fluorescencia de la tioflavina T (ThT). espectroscopia de fluorescencia de la tioflavina T (ThT).
- Microscopía de electrones de transmisión (TEM).
- Resonancia magnética nuclear de estado sólido (RMN).
Principales resultados:
- La siembra repetida amplifica selectivamente una estructura de fibril única y homogénea D23N-Aβ ((1-40) a partir de una mezcla polimórfica.
- La estructura de las fibrillas amplificadas es sensible a los factores ambientales como el pH, la temperatura y la agitación.
- Las estructuras fibrílicas finales adoptan predominantemente configuraciones paralelas de hojas β, lo que indica la metastabilidad de las estructuras antiparalelas.
- La intensidad de fluorescencia ThT es altamente dependiente de las variaciones estructurales de las fibrillas, incluso para el mismo polipéptido.
Conclusiones:
- Un protocolo de siembra repetido puede aislar eficazmente los polimorfos específicos de las fibrillas Aβ.
- Las condiciones ambientales influyen significativamente en la estructura final de las fibrillas D23N-Aβ.
- Las estructuras antiparalelas de la hoja β en las fibrillas Aβ son probablemente transitorias.
- La variabilidad de la fluorescencia ThT subraya la necesidad de una interpretación cuidadosa en la investigación amiloide.
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