Department of Pharmacology, University of Oslo and Oslo University Hospital, Postboks 1057, Blindern, NO-0316, OSLO, Norway.
Department of Medical Biochemistry and Microbiology, The Biomedical Center, University of Uppsala, Box 582, SE-751 23, Uppsala, Sweden.
Sci Rep. 2019 Mar 14;9(1):4600. doi: 10.1038/s41598-019-40999-4.
Amyloid-β (Aβ) is the main constituent of amyloid deposits in Alzheimer's disease (AD). The neuropathology is associated with neuroinflammation. Here, we investigated effects of systemic lipopolysaccharide (LPS)-treatment on neuroinflammation and Aβ deposition in AβPP-mice and double-transgenic mice with brain expression of AβPP and heparanase, an enzyme that degrades HS and generates an attenuated LPS-response. At 13 months of age, the mice received a single intraperitoneal injection of 50 µg LPS or vehicle, and were sacrificed 1.5 months thereafter. Aβ in the brain was analyzed histologically and biochemically after sequential detergent extraction. Neuroinflammation was assessed by CD45 immunostaining and mesoscale cytokine/chemokine ELISA. In single-transgenic mice, LPS-treatment reduced total Aβ deposition and increased Tween-soluble Aβ. This was associated with a reduced CXCL1, IL-1β, TNF-α-level and microgliosis, which correlated with amyloid deposition and total Aβ. In contrast, LPS did not change Aβ accumulation or inflammation marker in the double-transgenic mice. Our findings suggest that a single pro-inflammatory LPS-stimulus, if given sufficient time to act, triggers Aβ-clearance in AβPP-transgenic mouse brain. The effects depend on HS and heparanase.
淀粉样蛋白-β（Aβ）是阿尔茨海默病（AD）中淀粉样沉积物的主要成分。神经病理学与神经炎症有关。在这里，我们研究了全身脂多糖（LPS）处理对 AβPP 小鼠和具有大脑表达 AβPP 和硫酸乙酰肝素酶的双转基因小鼠的神经炎症和 Aβ 沉积的影响，该酶降解 HS 并产生减弱的 LPS 反应。在 13 个月大时，将小鼠接受 50μg LPS 或载体的单次腹腔内注射，并在 1.5 个月后处死。用顺序去污剂提取后，通过组织化学和生化方法分析大脑中的 Aβ。通过 CD45 免疫染色和中尺度细胞因子/趋化因子 ELISA 评估神经炎症。在单转基因小鼠中，LPS 处理减少了总 Aβ 沉积并增加了吐温可溶 Aβ。这与 CXCL1、IL-1β、TNF-α 水平降低和小胶质细胞增生有关，与淀粉样蛋白沉积和总 Aβ有关。相比之下，LPS 并未改变双转基因小鼠中的 Aβ 积累或炎症标志物。我们的研究结果表明，单次促炎 LPS 刺激，如果有足够的时间起作用，会触发 AβPP 转基因小鼠大脑中的 Aβ 清除。该效果取决于 HS 和肝素酶。
