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UAM (Universidad Autónoma de Madrid)

UAM (Universidad Autónoma de Madrid)

La Universidad Autónoma de Madrid es una universidad pública española, ubicada en Madrid y fundada en 1968, momento en que sus facultades estaban dispersas por diversos edificios de la capital española. En junio de 2018 la Universidad Autónoma de Madrid cumplirá sus primeros 50 años. Para celebrar este aniversario, la universidad prepara un programa conmemorativo que se desarrollará entre los años 2016 y 2019 e incluirá actividades abiertas a todo el conjunto de la sociedad. https://www.uam.es/

Nuevos avances en el tratamiento de la enfermedad de Alzheimer

Fuente: UAM Gazette | Publicado: 16-10-2017
Un equipo de científicos españoles y del Reino Unido, liderado desde el IIS del Hospital La Princesa - Universidad Autónoma de Madrid (UAM), ha descrito en Scientific Reports una nueva estrategia terapéutica para el tratamiento de la enfermedad de Alzheimer. Se trata de compuestos dirigidos a una combinación de dianas terapéuticas no convencionales que podrían suponer un avance significativo hacia un tratamiento efectivo para esta devastadora enfermedad.
Derechos: Representación artística. Pixabay.
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Debido a los fracasos continuos en 20 años, los paradigmas para el desarrollo de fármacos contra la enfermedad de Alzheimer están cambiando. Una nueva línea se apoya en la hipótesis de que los agregados proteicos característicos de esta enfermedad son consecuencia de procesos anteriores, como el estrés oxidativo y la neuroinflamación crónica del cerebro.

Desde hace cinco años, un equipo internacional, formado por científicos de la Universidad Autónoma de Madrid (UAM), el Instituto de Investigación Biomédica del Hospital la Princesa, la Universidad Complutense de Madrid y el University College London, viene desarrollando una estructura química basada en esta nueva aproximación.

Ahora, el equipo ha logrado desarrollar una innovadora familia de compuestos para el tratamiento de la enfermedad de Alzheimer. Estos compuestos, descritos en la revista Scientific Reports, fueron diseñados mediante técnicas de modelización por computación, lo que permitió incluir varias dianas terapéuticas en una sola estructura: la inducción de la vía de autodefensa celular frente a estrés oxidativo Nrf2-ARE, y la inhibición de la quinasa responsable de la aparición de agregados proteicos intracelulares (la enzima GSK3b que además participa en la activación de la neuroinflamación).

De acuerdo con los autores, esta es la primera vez que se describe una familia de compuestos con una combinación de actividades similar.



“Las actividades propuestas en la hipótesis de diseño fueron posteriormente demostradas en estudios in vitro, en los cuales los nuevos compuestos fueron capaces de reducir el estrés oxidativo, bloquear la neuroinflamación y evitar la formación de agregados aberrantes de proteína tau. La suma de estas actividades se tradujo en un potente efecto neuroprotector”, resalta el Dr. Rafael León, investigador principal del estudio.


Sistema de defensa intrínseco de las células: Vía Nrf2-ARE

Una de las características más prominentes de la enfermedad de Alzheimer es un aumento incontrolado del estrés oxidativo. El estrés oxidativo se define como la aparición de especies altamente reactivas de oxigeno o nitrógeno como consecuencia de la respiración celular. Por tanto, el estrés oxidativo es inherente a la vida, además de ser responsable del envejecimiento.

Para contrarrestar los efectos tóxicos de estas especies, las células han desarrollado un mecanismo propio de defensa, denominado “respuesta antioxidante de fase II”, y regulado por el factor de transcripción Nrf2. En la enfermedad de Alzheimer se ha demostrado que la defensa intrínseca de las neuronas es defectuosa, de forma que la célula no es capaz de regular los niveles de especies reactivas. Este fallo de regulación provoca un aumento descontrolado de estas especies que daña los componentes celulares, provocando finalmente la muerte celular.



Los compuestos desarrollados son capaces de activar el factor de transcripción Nrf2, ayudando a la célula a regular los niveles de especies reactivas, y evitando así la muerte neuronal observada en la enfermedad de Alzheimer.


No obstante, esta devastadora enfermedad se compone de multitud de procesos patológicos interconectados, de forma que, aunque se detenga una de estas vías, el proceso degenerativo sigue avanzando. Por ello, los compuestos desarrollados han sido diseñados para actuar sobre distintas rutas patológicas simultáneamente, lo que se conoce como “estrategia multidiana”.


Agregados proteicos y neuroinflamación

El avance del proceso degenerativo en la enfermedad de Alzheimer se caracteriza por un aumento de la neuroinflamación y la aparición de agregados intracelulares de proteína tau fosforilada, denominados ovillos neurofibrilares.

En ambos procesos, la quinasa GSK3b juega un papel esencial. Por un lado, interviene en las vías de activación de la neuroinflamación mediante activación de proteínas por fosforilación directa. Por otra parte, es la principal encargada de la fosforilación aberrante de la proteína tau que finalmente forma agregados tóxicos.

Teniendo en cuenta ambos procesos, el diseño de los nuevos derivados también se ha dirigido a incluir capacidad inhibitoria de esta quinasa. La inhibición de GSK3b está dirigida a reducir tanto la neuroinflamación como la formación de agregados tóxicos para las neuronas.


Referencia bibliográfica: Isabel Gameiro, Patrycja Michalska, Giammarco Tenti, Ángel Cores, Izaskun Buendia, Ana I. Rojo, Nikolaos D. Georgakopoulos, Jesús M. Hernández-Guijo, María Teresa Ramos, Geoffrey Wells, Manuela G. López, Antonio Cuadrado, J. Carlos Menéndez & Rafael León. Discovery of the first dual GSK3β inhibitor/Nrf2 inducer. A new multitarget therapeutic strategy for Alzheimer’s disease. Scientific Reports. DOI: 10.1038/srep45701
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