TY - JOUR
T1 - Increased neutrophils in inflammatory bowel disease accelerate the accumulation of amyloid plaques in the mouse model of Alzheimer’s disease
AU - Kaneko, Ryusei
AU - Matsui, Ako
AU - Watanabe, Mahiro
AU - Harada, Yoshihiro
AU - Kanamori, Mitsuhiro
AU - Awata, Natsumi
AU - Kawazoe, Mio
AU - Takao, Tomoaki
AU - Kobayashi, Yutaro
AU - Kikutake, Chie
AU - Suyama, Mikita
AU - Saito, Takashi
AU - Saido, Takaomi C.
AU - Ito, Minako
N1 - Funding Information:
We would like to thank Laboratory for Research Support, Medical Institute of Bioregulation (Kyushu University). We also thank Mayu Sogawa, Rinka Ito, Ayumi Okamura, Ayame Nagafuchi, and Tatsuya Yokota for their technical help.
Funding Information:
This work was supported by JSPS KAKENHI 21H02719, 21H00432, 21H05044, 21K19382, MOON SHOT 21zf0127003h, AMED-PRIME 22gm6210012, AMED- 22wm0425011, Research grant from the Chemo-Sero-Therapeutic Research Institute, the Kishimoto Family Foundation, the Tomizawa Jun-ichi, the Mitsubishi Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Takeda Science Foundation, the Uehara Memorial Foundation, the Naito Foundation, the Kanae Foundation, the SENSHIN Medical Research Foundation, the Inamori Foundation, the Foundation of Kinoshita Memorial Enterprise, the NOVARTIS Foundation (Japan) for the Promotion of Science, the Astellas Foundation for Research on Metabolic Disorders, the Inoue Research Award for Young Scientists.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
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U2 - 10.1186/s41232-023-00257-7
DO - 10.1186/s41232-023-00257-7
M3 - Article
AN - SCOPUS:85150696460
SN - 1880-9693
VL - 43
JO - Inflammation and Regeneration
JF - Inflammation and Regeneration
IS - 1
M1 - 20
ER -