La perturbation chronique du rythme circadien comme moteur de la pathologie tau médiée par l’inflammasome NLRP3 microglial dans la maladie d’Alzheimer : une proposition de recherche

Auteurs-es

  • Ayman Assaaoudi University of Ottawa, Ottawa, ON, Canada

DOI :

https://doi.org/10.18192/osurj.v5i2.8084

Résumé

La maladie d’Alzheimer (MA) touche plus de 55 millions de personnes dans le monde, et il n’existe toujours pas de traitement approuvé capable de modifier directement l’évolution de la maladie. Un facteur de risque connu est la perturbation du rythme circadien, c’est-à-dire l’horloge interne de 24 heures du corps. Cependant, on ne sait pas encore exactement comment cette perturbation contribue à l’accumulation de la protéine tau toxique dans le cerveau. Les cellules immunitaires du cerveau, appelées microglies, possèdent aussi leur propre horloge interne. Cette horloge est contrôlée par le complexe de protéines BMAL1/CLOCK. Lorsque cette horloge est perturbée, les microglies peuvent rester dans un état d’inflammation chronique. De façon séparée, l’activation d’une voie inflammatoire microgliale appelée inflammasome NLRP3 peut rendre la protéine tau anormalement phosphorylée. Cette étape est importante dans la formation des enchevêtrements neurofibrillaires, qui contribuent à la mort des neurones dans la MA. Cette proposition met donc en évidence un lien mécanique qui n’a pas encore été testé directement. L’hypothèse est que le décalage horaire chronique, utilisé en laboratoire comme modèle de perturbation circadienne, pourrait affaiblir le rythme de BMAL1 dans les microglies. Cela pourrait ensuite entraîner une activation non contrôlée de NLRP3 et accélérer la pathologie tau chez des souris P301S, un modèle de tauopathie. Cinq groupes seraient comparés, et le bloqueur pharmacologique de NLRP3, MCC950, serait utilisé comme approche de “sauvetage” afin de confirmer le lien de causalité. Ces résultats pourraient montrer qu’un facteur de mode de vie modifiable contribue directement à la MA et que NLRP3 dans les microglies est une cible thérapeutique prometteuse.

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Publié-e

2026-06-17

Numéro

Vol. 5 No. 2 (2026)

Rubrique

Research Proposals

Licence

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