Multi-transcriptomics reveals brain cellular responses to peripheral infection in Alzheimer's disease model mice [spatial transcriptomics]

Peripheral inflammation has been associated with various neurodegeneration, including Alzheimer's Disease (AD). In this study, we employed an AD mouse model nasally infected with Staphylococcus aureus to assess the impact of chronic or acute peripheral inflammation on brain transcriptome and amyloid pathology. The chronic exposure increased the diffuse and compact amyloid plaques and blood cytokine levels. Following a short-term exposure, single-cell and spatial transcriptomics uncovered cell type- and spatial-specific transcriptional changes indicating a dysregulation of the brain barriers, including the blood-brain and the blood-cerebrospinal fluid barriers. Brain macrophages exhibited increased Apoe expression and macrophage-specific genes were upregulated at ventricular areas of infected mice. In addition, we report an increase of disease associated microglia genes around the A? plaques, together with disbalances in neuronal expression in response to peripheral inflammation. Overall, results enlighten the mechanisms linking peripheral inflammation to AD. Overall design: We used an AD mouse model nasally infected with Staphylococcus aureus. mRNA-seq for whole brain was conducted following long-term treatment (16 weeks) , and scRNA-seq and visium spatial transcriptomics were peformed after 1-week acute peripheral inflammation.