Bacterial sepsis increases hippocampal fibrillar amyloid plaque load and neuroinflammation in a mouse model of Alzheimer's disease.
Bacterial sepsis increases hippocampal fibrillar amyloid plaque load and neuroinflammation in a mouse model of Alzheimer's disease.
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DOI：
10.1016/j.nbd.2021.105292
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发表时间：
2021-05
影响因子：
6.1
通讯作者：
Musiek ES
中科院分区：
文献类型：
--
作者：
Basak JM;Ferreiro A;Cohen LS;Sheehan PW;Nadarajah CJ;Kanan MF;Sukhum KV;Dantas G;Musiek ES
败血症是重症监护病房入院的主要原因，在幸存者中引起急性脑病和慢性脑功能障碍。败血症史也是未来痴呆症状发展的危险因素。类似的神经病理改变与败血症和阿尔茨海默病（AD）的认知能力下降有关，包括神经炎症、神经元死亡和突触丧失。淀粉样斑块病理是阿尔茨海默病最早的病理标志，在认知能力下降前10至20年出现，在30%的65岁以上人群中出现。由于脓毒症在老年人中也更为常见，我们假设脓毒症可能加剧淀粉样斑块沉积和斑块相关损伤，促进ad相关病理的进展。我们评估了大脑对败血症的反应是否通过驱动小鼠淀粉样蛋白沉积和神经炎症来调节ad相关的神经退行性改变。我们对ad相关β-淀粉样变性模型APP/ PS1-21小鼠进行盲肠结扎穿刺（CLP）诱导多微生物脓毒症。我们在斑块出现时（2个月大）进行CLP或假手术，并在存活小鼠CLP后2个月检查病理。脓毒症显著增加APP/ PS1-21小鼠海马纤维样淀粉样斑块的形成。脓毒症增强了斑块相关星形胶质细胞的激活和补体C4b基因在大脑中的表达，这两者都可能在调节淀粉样蛋白形成中发挥作用。CLP还引起APP/PS1小鼠肠道微生物组的大规模变化，这与前淀粉样变性和神经炎症状态有关。我们的研究结果表明，实验性脓毒症可以加剧淀粉样斑块沉积和斑块相关炎症，为老年脓毒症幸存者增加痴呆提供了潜在的机制。
Sepsis, a leading cause for intensive care unit admissions, causes both an acute encephalopathy and chronic brain dysfunction in survivors. A history of sepsis is also a risk factor for future development of dementia symptoms. Similar neuropathologic changes are associated with the cognitive decline of sepsis and Alzheimer’s disease (AD), including neuroinflammation, neuronal death, and synaptic loss. Amyloid plaque pathology is the earliest pathological hallmark of AD, appearing 10 to 20 years prior to cognitive decline, and is present in 30% of people over 65. As sepsis is also more common in older adults, we hypothesized that sepsis might exacerbate amyloid plaque deposition and plaque-related injury, promoting the progression of AD-related pathology. We evaluated whether the brain’s response to sepsis modulates AD-related neurodegenerative changes by driving amyloid deposition and neuroinflammation in mice. We induced polymicrobial sepsis by cecal ligation and puncture (CLP) in APP/PS1–21 mice, a model of AD-related β-amyloidosis. We performed CLP or sham surgery at plaque onset (2 months of age) and examined pathology 2 months after CLP in surviving mice. Sepsis significantly increased fibrillar amyloid plaque formation in the hippocampus of APP/PS1–21 mice. Sepsis enhanced plaque-related astrocyte activation and complement C4b gene expression in the brain, both of which may play a role in modulating amyloid formation. CLP also caused large scale changes in the gut microbiome of APP/PS1 mice, which have been associated with a pro-amyloidogenic and neuroinflammatory state. Our results suggest that experimental sepsis can exacerbate amyloid plaque deposition and plaque-related inflammation, providing a potential mechanism for increased dementia in older sepsis survivors.
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影响因子：
6.3
作者：
Iwashyna TJ;Cooke CR;Wunsch H;Kahn JM
通讯作者：
Kahn JM
DOI：
10.1038/ismej.2012.8
发表时间：
2012-08
期刊：
The ISME journal
影响因子：
--
作者：
通讯作者：
--
影响因子：
15.1
作者：
Erickson, Michelle A.;Banks, William A.
通讯作者：
Banks, William A.
影响因子：
48
作者：
Callahan BJ;McMurdie PJ;Rosen MJ;Han AW;Johnson AJ;Holmes SP
通讯作者：
Holmes SP
影响因子：
8.8
作者：
Barichello, T;Fortunato, JJ;Dal-Pizzol, F
通讯作者：
Dal-Pizzol, F