Kaneko Ryusei, Matsui Ako, Watanabe Mahiro, Harada Yoshihiro, Kanamori Mitsuhiro, Awata Natsumi, Kawazoe Mio, Takao Tomoaki, Kobayashi Yutaro, Kikutake Chie, Suyama Mikita, Saito Takashi, Saido Takaomi C, Ito Minako
Division of Allergy and Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Division of Bioinformatics, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Inflamm Regen. 2023 Mar 15;43(1):20. doi: 10.1186/s41232-023-00257-7.
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. App 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.
Wild-type and App 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.
An increase in aggregated Aβ was observed in the brains of App 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.
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.
阿尔茨海默病（AD）是一种神经退行性疾病，其特征是随着年龄增长，β淀粉样蛋白（Aβ）聚集体和磷酸化tau蛋白出现并积累。Aβ作为老年斑的主要成分，其聚集与疾病进展密切相关。App小鼠是一种AD小鼠模型，在淀粉样前体蛋白基因中有三个家族性AD突变，表现出年龄依赖性的AD样症状和病理特征。肠-脑相互作用已引起广泛关注，炎症性肠病（IBD）与人类患痴呆症尤其是AD的风险较高有关。然而，AD中肠道炎症对大脑的潜在机制和影响仍 largely未知。因此，我们旨在研究肠道炎症对AD发病机制的影响。
给三个月大的野生型和App小鼠喂食含2%硫酸葡聚糖钠（DSS）的水以诱导结肠炎。使用单细胞RNA测序（scRNA-seq）分析大脑中的免疫细胞，并通过免疫组织化学分析大脑中Aβ蛋白的聚集情况。
在患有急性肠道炎症的App小鼠大脑中观察到Aβ聚集增加。对大脑中免疫细胞进行详细的scRNA-seq分析表明，急性肠炎后大脑中的中性粒细胞增加。通过抗体清除中性粒细胞可抑制因肠道炎症而增加的Aβ积累。
这些结果表明，急性结肠炎发生时中性粒细胞浸润AD脑实质，且这种浸润与疾病进展显著相关。因此，我们提出以中性粒细胞为靶点的治疗方法可以减少早期AD中观察到的Aβ积累，并预防因结肠炎导致的AD风险增加。
