Stool-derived extracellular vesicles increase inflammasome signaling and regulate the gut-brain axis after stroke in Alzheimer's disease transgenic mice

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Patients with Alzheimer's disease (AD) suffering from post-stroke gut dysfunction present with worsened neurological outcomes. This study investigated the role of stool-derived extracellular vesicle (EV)-mediated inflammasome signaling in the gut-brain axis following photothrombotic stroke (PTS) in aged 3xTg- AD and wildtype (WT) mice. Western Blot and immunohistochemical analyses evaluated inflammasome signaling proteins, Gasdermin D (GSDMD), and Aβ in intestinal and cortical tissues. Gut permeability was measured using a FITC-dextran assay 3 days post PTS. Adoptive transfer experiments assessed the impact of stool-derived EVs from PTS mice on inflammasome signaling in recipient naïve 3xTg and WT mice. At 3 days, 3xTg-PTS mice demonstrated significantly impaired sensorimotor Rotarod performance compared to WT-PTS mice. Both WT and 3xTg PTS mice had deficits compared to 3xTg and WT sham mice using the Open Field or Novel Object Recognition tests. Compared to WT- PTS mice, 3xTg-PTS mice had disrupted gut morphology at 1-month post-PTS, as well as increased gut permeability at 72 h. Immunohistochemical analysis also revealed activated microglial morphology and presence of GSDMD and Aβ in the brain and intestines post-PTS in 3xTg and WT mice. Adoptive transfer of stool-derived EVs from PTS mice to WT mice induced elevated levels of inflammasome signaling proteins in recipient cerebral cortices. These findings indicate an important role of stool-derived EV inflammasome signaling and pyroptosis in disruption of the bidirectional gut-brain axis after stroke leading to exacerbation of AD pathology in aged WT and 3xTg mice. Schematic showing that after stroke in preexisting AD, serum-derived EVs containing inflammasome proteins are released into the circulation and taken up into the gut. In turn, increased gut permeability and pyroptosis leads to the release of stool-derived EVs from the gut containing inflammasome proteins that are released into the circulation and taken up by the brain causing increased neuroinflammation, pyroptosis, and worsened neurological function. • Gut-brain axis dysfunction can worsenneurological function after stroke and in Alzheimer's Disease (AD). • Inflammasome signaling and pyroptosis contribute to gut-brain axis dysfunction after stroke in AD. • Amyloid-beta pathology increases with aging after stroke without genetic predisposition to AD. • Stool-derived Extracellular Vesicles (EVs) serve as a signaling mechanism for gut-brain axis dysfunction after stroke and AD.

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