Sepsis exacerbates Alzheimer's disease pathophysiology, modulates the gut microbiome, increases neuroinflammation and amyloid burden

While our understanding of the molecular biology of Alzheimer's disease (AD) has grown, the etiology of the disease, especially the involvement of peripheral infection, remains a challenge. In this study, we hypothesize that peripheral infection represents a risk factor for AD pathology. To test our hypothesis, APP/PS1 mice underwent cecal ligation and puncture (CLP) surgery to develop a polymicrobial infection or non-CLP surgery. Mice were euthanized at 3, 30, and 120 days after surgery to evaluate the inflammatory mediators, glial cell markers, amyloid burden, gut microbiome, gut morphology, and short-chain fatty acids (SCFAs) levels. The novel object recognition (NOR) task was performed 30 and 120 days after the surgery, and sepsis accelerated the cognitive decline in APP/PS1 mice at both time points. At 120 days, the insoluble A & beta; increased in the sepsis group, and sepsis modulated the cytokines/chemokines, decreasing the cytokines associated with brain homeostasis IL-10 and IL-13 and increasing the eotaxin known to influence cognitive function. At 120 days, we found an increased density of IBA-1-positive microglia in the vicinity of A & beta; dense-core plaques, compared with the control group confirming the predictable clustering of reactive glia around dense-core plaques within 15 & mu;m near A & beta; deposits in the brain. In the gut, sepsis negatively modulated the & alpha;- and & beta;-diversity indices evaluated by 16S rRNA sequencing, decreased the levels of SCFAs, and significantly affected ileum and colon morphology in CLP mice. Our data suggest that sepsis-induced peripheral infection accelerates cognitive decline and AD pathology in the AD mouse model.

Automated summary

In this study, it was found that peripheral infection may be a risk factor for Alzheimer's disease pathology, and infection can accelerate cognitive decline and AD pathology. By inducing a polymicrobial infection in APP/PS1 mice through cecal ligation and puncture surgery, the study showed that sepsis led to increased Aβ deposition and activation of microglia around Aβ plaques in the brain. Furthermore, sepsis affected gut microbiome composition and structure, as well as short-chain fatty acid levels.