Title : Systemic inflammation and neuroinflammation in alzheimer’s disease: An unexplored relationship
Abstract:
Growing evidence suggests a link between systemic inflammation and cognitive decline. Studies in cognitively healthy individuals have demonstrated an association between low-grade systemic inflammation, and accelerated cognitive decline. Furthermore, some research indicates a potential role for systemic inflammation in the pathogenesis of Alzheimer's disease (AD). Preclinical models exploited for the investigation of this link have shown how acute systemic inflammation can exacerbate neurodegenerative processes in the context of existing neurodegeneration, leading to accelerated disease progression. While the precise mechanisms remain under investigation, it is now clear that systemic inflammation, both acute and chronic, can trigger a cascade of events, which, in turn, can influence brain microenvironment. Given the mounting evidence linking various systemic inflammatory conditions to AD risk, we hypothesized that acute systemic inflammation in the pre-symptomatic phase would influence in the long term the timing and the degree of cognitive decline. One of the risk factors associated to a higher prevalence of AD is the diagnosis of inflammatory bowel disease as described by different epidemiological and preclinical studies, but the mechanisms at the basis of this link are still unclear. To help bridge this gap, we induced acute colitis by dextran sulfate sodium (DSS) administration in young, presymptomatic/preplaque Tg2576 mice (carrying the Swesidish APP mutation) and in C57BL6 wild type mice, to model human IBD and evaluate the effects of this acute peripheral inflammation on the age of cognitive symptoms onset and/or on its worsening. Results indicated that gut inflammation in 3 months old Tg2576 mice anticipated the learning and memory impairment, which usually appears in Tg2576 mice starting from 6 months of age. Gut microbiota/microbiome dysbiosis, as well as peripheral inflammation, is thought to have an active role in the natural course of AD, acting way before the onset of the first clinical symptoms. Following DSS-induced gut inflammation, we observed an altered Firmicutes/Bacterioides ratio in Tg2576 but not in WT, suggesting an anticipated aging of the microbiota profile in Tg2576 recovered from gut inflammation, in line with what observed in IBD patients. Finally, we focused on hippocampal tissue as it is the main player in the symptomatology observed in behavioral tests and we found significantly altered inflammation- and neuroinflammation-related parameters in 3-months old Tg2576, with a rapid progression towards a worsening of the scenario at the age of 5.5 months. Our results points towards an astroglial dysfunction as a possible contributor for AD onset, with a functional impairment in astrocyte population as a consequence to the gut inflammation. This approach can be a valuable tool to dissect the impact of known or possible risk factors for Alzheimer’s disease, helping in the understanding of the intricate interplay between peripheral inflammation, neuroinflammation and disease onset, which is crucial for the unveiling of the heterogeneity of AD with the aim to develop effective therapeutic strategies.
