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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE218361 | GEO | 2023/07/15

REPOSITORIES: GEO

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

Project description:Peripheral inflammation has been linked to various neurodegenerative disorders, including Alzheimer's disease (AD). Here we perform bulk, single-cell, and spatial transcriptomics in APP/PS1 mice intranasally exposed to Staphylococcus aureus to determine how low-grade peripheral infection affects brain transcriptomics and AD-like pathology. Chronic exposure led to increased amyloid plaque burden and plaque-associated microglia, significantly affecting the transcription of brain barrier-associated cells, which resulted in barrier leakage. We reveal cell-type- and spatial-specific transcriptional changes related to brain barrier function and neuroinflammation during the acute infection. Both acute and chronic exposure led to brain macrophage-associated responses and detrimental effects in neuronal transcriptomics. Finally, we identify unique transcriptional responses at the amyloid plaque niches following acute infection characterized by higher disease-associated microglia gene expression and a larger effect on astrocytic or macrophage-associated genes, which could facilitate amyloid and related pathologies. Our findings provide important insights into the mechanisms linking peripheral inflammation to AD pathology.

| S-EPMC10530196 | biostudies-literature

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

Project description: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.

2023-07-15 | GSE218360 | GEO

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

2023-07-15 | GSE218352 | GEO

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

2023-07-15 | GSE218346 | GEO

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

Project description:Multi-transcriptomics reveals brain cellular responses to peripheral infection in Alzheimer's disease model mice

| PRJNA903210 | ENA

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

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

| PRJNA903211 | ENA

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

Project description:Multi-transcriptomics reveals brain cellular responses to peripheral infection in Alzheimer's disease model mice [RNA-seq]

| PRJNA903187 | ENA

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

Project description:Multi-transcriptomics reveals brain cellular responses to peripheral infection in Alzheimer's disease model mice [scRNA-seq]

| PRJNA903193 | ENA

Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease.

Project description:Glia have been implicated in Alzheimer's disease (AD) pathogenesis. Variants of the microglia receptor triggering receptor expressed on myeloid cells 2 (TREM2) increase AD risk, and activation of disease-associated microglia (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene-expression changes associated with AD pathology and TREM2 in 5XFAD mice and in human AD by single-nucleus RNA sequencing. We confirmed the presence of Trem2-dependent DAM and identified a previously undiscovered Serpina3n+C4b+ reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral-nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less evident in TREM2-R47H and TREM2-R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences.

| S-EPMC6980793 | biostudies-literature

Cellular transcriptional alterations of peripheral blood in Alzheimer's disease.

Project description:BackgroundAlzheimer's disease (AD), a progressive neurodegenerative disease, is the most common cause of dementia worldwide. Accumulating data support the contributions of the peripheral immune system in AD pathogenesis. However, there is a lack of comprehensive understanding about the molecular characteristics of peripheral immune cells in AD.MethodsTo explore the alterations of cellular composition and the alterations of intrinsic expression of individual cell types in peripheral blood, we performed cellular deconvolution in a large-scale bulk blood expression cohort and identified cell-intrinsic differentially expressed genes in individual cell types with adjusting for cellular proportion.ResultsWe detected a significant increase and decrease in the proportion of neutrophils and B lymphocytes in AD blood, respectively, which had a robust replicability across other three AD cohorts, as well as using alternative algorithms. The differentially expressed genes in AD neutrophils were enriched for some AD-associated pathways, such as ATP metabolic process and mitochondrion organization. We also found a significant enrichment of protein-protein interaction network modules of leukocyte cell-cell activation, mitochondrion organization, and cytokine-mediated signaling pathway in neutrophils for AD risk genes including CD33 and IL1B. Both changes in cellular composition and expression levels of specific genes were significantly associated with the clinical and pathological alterations. A similar pattern of perturbations on the cellular proportion and gene expression levels of neutrophils could be also observed in mild cognitive impairment (MCI). Moreover, we noticed an elevation of neutrophil abundance in the AD brains.ConclusionsWe revealed the landscape of molecular perturbations at the cellular level for AD. These alterations highlight the putative roles of neutrophils in AD pathobiology.

| S-EPMC9422129 | biostudies-literature

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