Ryusei Kaneko, Ako Matsui, Mahiro Watanabe, Yoshihiro Harada, Mitsuhiro Kanamori, Natsumi Awata, Mio Kawazoe, Tomoaki Takao, Yutaro Kobayashi, Chie Kikutake, Mikita Suyama, Takashi Saito, Takaomi C Saido, Minako Ito
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Gut-brain interactions have attracted considerable attention and inflammatory bowel disease (IBD) has been associated with a higher risk of dementia, especially AD, in humans. However, the underlying mechanisms and the effects of intestinal inflammation on the brain in AD remain largely unknown. Therefore, we aimed to investigate the effects of intestinal inflammation on AD pathogenesis.</p><p><strong>Methods: </strong>Wild-type and App<sup>NL-G-F</sup> mice at three months of age were fed with water containing 2% dextran sulfate sodium (DSS) to induce colitis. Immune cells in the brain were analyzed using single-cell RNA sequencing (scRNA-seq) analysis, and the aggregation of Aβ protein in the brain was analyzed via immunohistochemistry.</p><p><strong>Results: </strong>An increase in aggregated Aβ was observed in the brains of App<sup>NL-G-F</sup> mice with acute intestinal inflammation. Detailed scRNA-seq analysis of immune cells in the brain showed that neutrophils in the brain increased after acute enteritis. Eliminating neutrophils by antibodies suppressed the accumulation of Aβ, which increased because of intestinal inflammation.</p><p><strong>Conclusion: </strong>These results suggest that neutrophils infiltrate the AD brain parenchyma when acute colitis occurs, and this infiltration is significantly related to disease progression. Therefore, we propose that neutrophil-targeted therapies could reduce Aβ accumulation observed in early AD and prevent the increased risk of AD due to colitis.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":null,"pages":null},"PeriodicalIF":5.0000,"publicationDate":"2023-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10015716/pdf/","citationCount":"2","resultStr":"{\"title\":\"Increased neutrophils in inflammatory bowel disease accelerate the accumulation of amyloid plaques in the mouse model of Alzheimer's disease.\",\"authors\":\"Ryusei Kaneko, Ako Matsui, Mahiro Watanabe, Yoshihiro Harada, Mitsuhiro Kanamori, Natsumi Awata, Mio Kawazoe, Tomoaki Takao, Yutaro Kobayashi, Chie Kikutake, Mikita Suyama, Takashi Saito, Takaomi C Saido, Minako Ito\",\"doi\":\"10.1186/s41232-023-00257-7\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Alzheimer's disease (AD) is one of the neurodegenerative diseases and characterized by the appearance and accumulation of amyloid-β (Aβ) aggregates and phosphorylated tau with aging. 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引用次数: 2
摘要
背景:阿尔茨海默病(AD)是一种神经退行性疾病,其特征是淀粉样蛋白-β (Aβ)聚集体和磷酸化tau蛋白随着年龄的增长而出现和积累。老年斑的主要成分Aβ的聚集与疾病进展密切相关。AppNL-G-F小鼠是一种AD小鼠模型,在淀粉样蛋白-β前体基因中有三个家族性AD突变,并表现出年龄依赖性AD样症状和病理。肠-脑相互作用引起了相当大的关注,炎症性肠病(IBD)与人类痴呆症,特别是阿尔茨海默病的高风险相关。然而,阿尔茨海默病的潜在机制和肠道炎症对大脑的影响在很大程度上仍然未知。因此,我们旨在探讨肠道炎症对AD发病机制的影响。方法:3月龄野生型和AppNL-G-F小鼠灌胃2%葡聚糖硫酸钠(DSS)水诱导结肠炎。采用单细胞RNA测序(scRNA-seq)分析脑内免疫细胞,免疫组织化学分析脑内Aβ蛋白聚集。结果:急性肠道炎症小鼠apnl - g - f大鼠脑内聚集性Aβ升高。大脑中免疫细胞的详细scRNA-seq分析显示,急性肠炎后大脑中的中性粒细胞增加。通过抗体消除中性粒细胞抑制了由于肠道炎症而增加的Aβ的积累。结论:急性结肠炎发生时,嗜中性粒细胞浸润AD脑实质,其浸润与疾病进展有显著关系。因此,我们建议中性粒细胞靶向治疗可以减少早期AD中观察到的Aβ积累,并防止结肠炎引起AD的风险增加。
Increased neutrophils in inflammatory bowel disease accelerate the accumulation of amyloid plaques in the mouse model of Alzheimer's disease.
Background: Alzheimer's disease (AD) is one of the neurodegenerative diseases and characterized by the appearance and accumulation of amyloid-β (Aβ) aggregates and phosphorylated tau with aging. The aggregation of Aβ, which is the main component of senile plaques, is closely associated with disease progression. AppNL-G-F mice, a mouse model of AD, have three familial AD mutations in the amyloid-β precursor gene and exhibit age-dependent AD-like symptoms and pathology. Gut-brain interactions have attracted considerable attention and inflammatory bowel disease (IBD) has been associated with a higher risk of dementia, especially AD, in humans. However, the underlying mechanisms and the effects of intestinal inflammation on the brain in AD remain largely unknown. Therefore, we aimed to investigate the effects of intestinal inflammation on AD pathogenesis.
Methods: Wild-type and AppNL-G-F mice at three months of age were fed with water containing 2% dextran sulfate sodium (DSS) to induce colitis. Immune cells in the brain were analyzed using single-cell RNA sequencing (scRNA-seq) analysis, and the aggregation of Aβ protein in the brain was analyzed via immunohistochemistry.
Results: An increase in aggregated Aβ was observed in the brains of AppNL-G-F mice with acute intestinal inflammation. Detailed scRNA-seq analysis of immune cells in the brain showed that neutrophils in the brain increased after acute enteritis. Eliminating neutrophils by antibodies suppressed the accumulation of Aβ, which increased because of intestinal inflammation.
Conclusion: These results suggest that neutrophils infiltrate the AD brain parenchyma when acute colitis occurs, and this infiltration is significantly related to disease progression. Therefore, we propose that neutrophil-targeted therapies could reduce Aβ accumulation observed in early AD and prevent the increased risk of AD due to colitis.
期刊介绍:
Inflammation and Regeneration is the official journal of the Japanese Society of Inflammation and Regeneration (JSIR). This journal provides an open access forum which covers a wide range of scientific topics in the basic and clinical researches on inflammation and regenerative medicine. It also covers investigations of infectious diseases, including COVID-19 and other emerging infectious diseases, which involve the inflammatory responses.
Inflammation and Regeneration publishes papers in the following categories: research article, note, rapid communication, case report, review and clinical drug evaluation.