Alzheimer's Disease-Derived Outer Membrane Vesicles Exacerbate Cognitive Dysfunction, Modulate the Gut Microbiome,...

Although our understanding of the molecular biology of Alzheimer's disease (AD) continues to improve, the etiology of the disease, particularly the involvement of gut microbiota disturbances, remains a challenge. Outer membrane vesicles (OMVs) play a key role in central nervous system diseases, but the impact of OMVs on AD progression remains unclear. In this study, we hypothesized that AD-derived OMVs (OMVs^AD) were a risk factor in AD pathology. To test our hypothesis, young APP/PS1 mice (AD mice) were given OMVs^AD by gavage. Young AD mice were euthanized 120 days after gavage to assess the intestinal barrier, gut microbiota diversity, mediators of neuroinflammation, glial markers, amyloid burden, and short-chain fatty acid (SCFA) levels. Our results showed that OMVs^AD accelerated cognitive dysfunction after 120 days of intragastric administration. Morris water maze experiment and new object recognition test showed that OMVs^AD caused significantly poorer spatial ability learning and memory of the AD mice. We observed the OMVs^AD-treated APP/PS1 mice display OMVs disrupting the intestinal barrier compared with controls of normal human-derived OMVs. Compared with the OMVs^HC group, claudin-5 and ZO-1 related to the intestinal barrier were significantly downregulated in the OMVs^AD group. The OMVs^AD activate microglia in the cerebral cortex and hippocampus of AD mice, and the levels of IL-1β, IL-6, TNF-α, and NF-Κb were upregulated. We also found that OMVs^AD increased Aβ production. 16S rRNA sequencing showed that OMVs^AD negatively regulated the α- and β-diversity index of intestinal flora and reduced the levels of SCFA. OMVs^AD may change the intestinal flora of young AD, damage the intestinal mucosa and blood-brain barrier, and accelerate AD neuropathological damage.