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Ciencia básica y patogénesis

Mikaila Ann Bantugan1, Roberta Diaz Brinton1

  • 1University of Arizona, Tucson, AZ, USA.

Alzheimer's & dementia : the journal of the Alzheimer's Association
|December 25, 2025
PubMed
Resumen

Los ratones hembra con la variante genética APOE4 muestran un aumento de la neuroinflamación y la disfunción mitocondrial a través de la vía cGAS-STING, lo que sugiere un mayor riesgo de Alzheimer en las mujeres.

Palabras clave:
AlzheimerAPOE4neuroinflamacióndisfunción mitocondrialcGAS-STINGsexoratonesgenética

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Área de la Ciencia:

  • Neurociencia
  • Genética
  • Inmunología

Sus antecedentes:

  • La disfunción mitocondrial y la neuroinflamación son signos tempranos de la enfermedad de Alzheimer (EA).
  • La vía cGAS-STING, implicada en la inmunidad innata, desempeña un papel en la patogénesis de la EA.
  • El genotipo APOE4 y el sexo femenino pueden empeorar la disfunción mitocondrial y la neuroinflamación a través de la señalización cGAS-STING.

Objetivo del estudio:

  • Investigar las asociaciones específicas del sexo y del APOE con la disfunción mitocondrial y la neuroinflamación.
  • Examinar el papel de la vía cGAS-STING en estos procesos dentro de un modelo genético de riesgo de EA.

Principales métodos:

  • Se utilizaron ratones humanizados APP y APOE3/3 o APOE4/4 de 18 meses de edad.
  • Se empleó secuenciación de ARN masiva (RNA-seq) en tejido del hipocampo.
  • Se utilizó análisis de enriquecimiento de conjuntos de genes, análisis de vías de Ingenuity, inmunohistoquímica y Western blot para evaluar vías y señalización.

Principales resultados:

  • Las ratonas hAPP/hAPOE4 exhibieron mayor neuroinflamación, señalización cGAS-STING y disfunción mitocondrial en comparación con los ratones machos.
  • Las diferencias sexuales fueron menos pronunciadas en los ratones hAPP/hAPOE3.
  • Una interacción significativa entre el sexo y el genotipo APOE afectó la neuroinflamación, la disfunción mitocondrial y la señalización cGAS-STING.

Conclusiones:

  • Se observaron diferencias sexuales consistentes en las vías de neuroinflamación y mitocondriales.
  • El genotipo APOE influyó en las firmas neuroinflamatorias, especialmente en las hembras.
  • La señalización elevada de cGAS-STING en ratonas hAPP/hAPOE4 puede aumentar el riesgo de EA en mujeres, lo que subraya la necesidad de considerar el sexo y el genotipo en la investigación de la EA.