Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Cell Rep. 2023 Jul 25;42(7):112785. doi: 10.1016/j.celrep.2023.112785. Epub 2023 Jul 11.
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.
外周炎症与各种神经退行性疾病有关，包括阿尔茨海默病（AD）。在这里，我们对 APP/PS1 小鼠进行了批量、单细胞和空间转录组学研究，这些小鼠经鼻腔暴露于金黄色葡萄球菌，以确定低度外周感染如何影响大脑转录组学和 AD 样病理学。慢性暴露导致淀粉样斑块负担增加和斑块相关小胶质细胞显著增加，这显著影响了与血脑屏障相关的细胞的转录，从而导致了屏障渗漏。我们揭示了与脑屏障功能和神经炎症相关的细胞类型和空间特异性转录变化，这些变化发生在急性感染期间。急性和慢性暴露均导致大脑巨噬细胞相关反应和神经元转录组学的有害影响。最后，我们在急性感染后在淀粉样斑块龛位中发现了独特的转录反应，其特征是疾病相关小胶质细胞基因表达更高，对星形胶质细胞或巨噬细胞相关基因的影响更大，这可能促进淀粉样蛋白和相关病理。我们的研究结果为外周炎症与 AD 病理学之间的机制提供了重要的见解。
