Alzheimer’s disease (AD), a progressive neurodegenerative disorder characterized by memory loss and cognitive decline, is a major cause of death and disability among the older population. Despite decades of scientific research, the underlying etiological triggers are unknown. Recent studies suggested that gut microbiota can influence AD progression; however, potential mechanisms linking the gut microbiota with AD pathogenesis remain obscure. In the present study, we provided a potential mechanistic link between dysbiotic gut microbiota and neuroinflammation associated with AD progression. Using a mouse model of AD, we discovered that unfavorable gut microbiota are correlated with abnormally elevated expression of gut NLRP3 and lead to peripheral inflammasome activation, which in turn exacerbates AD-associated neuroinflammation. To this end, we observe significantly altered gut microbiota compositions in young and old 5xFAD mice compared to age-matched non-transgenic mice. Moreover, 5xFAD mice demonstrated compromised gut barrier function as evident from the loss of tight junction and adherens junction proteins compared to non-transgenic mice. Concurrently, we observed increased expression of NLRP3 inflammasome and IL-1β production in the 5xFAD gut. Consistent with our hypothesis, increased gut–microbial–inflammasome activation is positively correlated with enhanced astrogliosis and microglial activation, along with higher expression of NLRP3 inflammasome and IL-1β production in the brains of 5xFAD mice. These data indicate that the elevated expression of gut–microbial–inflammasome components may be an important trigger for subsequent downstream activation of inflammatory and potentially cytotoxic mediators, and gastrointestinal NLRP3 may promote NLRP3 inflammasome-mediated neuroinflammation. Thus, modulation of the gut microbiota may be a potential strategy for the treatment of AD-related neurological disorders in genetically susceptible hosts.

Potentiel translationnel d'une méthodologie basée sur des écrans tactiles pour évaluer les capacités cognitives chez la souris: Ce travail visait à évaluer le potentiel d’une méthodologie innovante récemment adaptée à la Souris sur la base de tests neuropsychologiques utilisés en clinique humaine. Après optimisation de 3 tâches (PAL, VMCL, PVD) ciblant différentes fonctions cognitives chez l’animal, nos études ont établi : (1) l’existence possible d’interférences proactives lors d’apprentissages consécutifs ; (2) l’absence de déficit d’acquisition chez les souris de la lignée Tg2576 (modèle transgénique de la maladie d’Alzheimer), quelle que soit l’étendue de la charge amyloïde ; (3) l’implication spécifique du striatum dorsal lors de l’acquisition des tâches de VMCL et PAL, et celle de l’hippocampe lors du rappel de cette dernière tâche. Ces derniers résultats suggèrent qu’en dépit des efforts déployés pour s’assurer du caractère translationnel d’une tâche cognitive dans le paradigme du touchscreen, certaines adaptations inhérentes à chaque espèce influencent profondément les bases neurobiologiques associées.