Alterations in the Gut-Microbial-Inflammasome-Brain Axis in a Mouse Model of Alzheimer’s Disease

Abstract

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.

Microbiota in neuroinflammation and synaptic dysfunction: a focus on Alzheimer’s disease

“…Indeed, analogous alterations are still evident at the overt stage of pathology (15 months of age). Consistently, this study found reduced Firmicutes / Bacteroidetes ratio in the gut of 5xFAD mice at both ages (5 and 15 months) concurrently with increased NLRP3 inflammasome and IL-1β production, which were positively correlated with astrogliosis and microgliosis along with increased cerebral NLRP3 inflammasome and IL-1β [ 109 ].…”

Lactobacillus plantarum PS128 prevents cognitive dysfunction in Alzheimer’s disease mice by modulating propionic acid levels, glycogen synthase kinase 3 beta activity, and gliosis

“…In this study, we assessed the effect of PS128 on the icv-STZ-treated 3 × Tg-AD model and showed that longterm supplementation with PS128 prevented cognitive dysfunction induced by icv-STZ in the 3 × Tg-AD male mice. The beneficial effects of PS128 supplementation on attenuating cognitive deficits were consistent with many other probiotic studies [14,[64][65][66][67]. Therefore, we suggest that PS128 supplementation is safe and has the potential to prevent cognitive dysfunction in individuals with AD.…”

Curcuma phaeocaulis Inhibits NLRP3 Inflammasome in Macrophages and Ameliorates Nanoparticle-Induced Airway Inflammation in Mice

“…In addition, the in vitro effects of C. phaeocaulis translate into a decrease in IL-1β levels and inflammatory cell infiltration in an animal model of airway inflammation caused by nanoparticles. Considering the fact that NLRP3 inflammasome is mechanistically linked to diverse pathophysiological conditions, including insulin resistance and neuroinflammation [ 17 , 18 ], it will be scientifically worthwhile to evaluate C. phaeocaulis extract in other animal models of diseases associated with excessive activation of NLRP3 inflammasome.…”