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

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 bra...

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Bibliographic Details
Published in:	Cell reports (Cambridge) Vol. 42; no. 7; p. 112785
Main Authors:	Lu, Yi, Saibro-Girardi, Carolina, Fitz, Nicholas Francis, McGuire, Mikayla Ranae, Ostach, Mary Ann, Mamun-Or-Rashid, A.N.M., Lefterov, Iliya, Koldamova, Radosveta
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 25-07-2023 Elsevier
Subjects:	Alzheimer Disease - metabolism Alzheimer’s disease Amyloid beta-Peptides - metabolism Amyloid beta-Protein Precursor - metabolism amyloid plaques Animals blood-brain barrier blood-cerebrospinal fluid barrier Brain - metabolism CP: Immunology CP: Neuroscience Disease Models, Animal Inflammation - pathology Mice Mice, Transgenic Microglia - metabolism microglia barrier peripheral inflammation Plaque, Amyloid - metabolism Transcriptome - genetics blood-brain barrier CP: Immunology blood-cerebrospinal fluid barrier Alzheimer’s disease CP: Neuroscience peripheral inflammation microglia barrier amyloid plaques
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Summary:	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. [Display omitted] •Peripheral bacterial infection affects brain transcriptomics and AD-like pathology•Transcriptional changes in brain-barrier-related cell types and leakage•Increased amyloid pathology and plaque-associated microglia•Unique transcriptional responses around amyloid plaques Lu et al. studied how low-grade peripheral infection affects brain transcriptomics in a mouse model of AD using multi-transcriptomics. Chronic exposure affects brain-barrier-associated cells and causes barrier leakage. Unique transcriptional responses occur in the amyloid plaque microenvironment, affecting microglia, astrocyte, and macrophage-related genes.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AUTHOR CONTRIBUTIONS Conceptualization, R.K., I.L., and N.F.F.; methodology, Y.L., C.S.-G., and N.F.F.; investigation, Y.L., C.S.-G., N.F.F., M.R.M., and M.A.O.; formal analysis, Y.L., C.S.-G., and N.F.F.; visualization, Y.L., C.S.-G., N.F.F., and A.N.M.M.-O.-R.; writing – original draft, Y.L., C.S.-G., and N.F.F.; writing – review & editing, R.K. and I.L.; supervision, R.K. and I.L.; project administration, R.K. and I.L.; resources, R.K. and I.L.; funding acquisition, R.K. and I.L.
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2023.112785