La disfunción de la Autofagia en la enfermedad del Alzheimer: Bioquímica y futuro terapéutico
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La Enfermedad de Alzheimer (AD), la cual es la principal causa de demencia, está caracterizada por la acumulación de β-amiloide y ovillos neurofibrilares, que causan deterioro cognitivo. En América Latina y el Caribe, la AD representa entre el 50% y el 84% de los casos de demencia, con proyecciones que indican un aumento a 13.7 millones de casos para 2050. El proceso de la autofagia celular, un proceso vital que mantiene la homeostasis al degradar células dañadas, es esencial para la salud neuronal. La disfunción de la autofagia se relaciona con la acumulación de proteínas mal plegadas en la AD. A pesar de que la autofagia se activa inicialmente como respuesta protectora frente a β-amiloide, su acumulación bloquea la degradación lisosómica, lo que resulta en la formación de oligómeros neurotóxicos y placas amiloides, causando inflamación y daño neuronal. Alteraciones en proteínas clave como Beclin 1, PICALM y PSEN-1 agravan la acumulación de Aβ, afectando la producción de ATP y contribuyendo a la neurodegeneración. La eficacia de los tratamientos actuales sigue siendo objeto de debate en la comunidad científica debido a las limitaciones que estos presentan, incluyendo la dificultad de replicación de la enfermedad humana en modelos animales, la penetración insuficiente en el sistema nervioso central de los tratamientos y sus posibles efectos adversos. De esta forma, su futuro terapéutico se enfoca principalmente en ampliar los ensayos clínicos estudiando distintas rutas patológicas y enfocándose en biomarcadores para la detección temprana de la enfermedad.
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