Chronic colitis exacerbates NLRP3-dependent neuroinflammation and cognitive impairment in middle-aged brain
Abstract Background Neuroinflammation is a major driver of age-related brain degeneration and concomitant functional impairment. In patients with Alzheimer’s disease, the most common form of age-related dementia, factors that enhance neuroinflammation may exacerbate disease progression, in part by i...
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doaj-7836ed0b0e8a4a88be2aacbae3657ae12021-07-11T11:47:05ZengBMCJournal of Neuroinflammation1742-20942021-07-0118111710.1186/s12974-021-02199-8Chronic colitis exacerbates NLRP3-dependent neuroinflammation and cognitive impairment in middle-aged brainXiao-fei He0Li-li Li1Wen-biao Xian2Ming-yue Li3Li-ying ZhangJing-hui Xu4Zhong Pei5Hai-qing Zheng6Xi-quan Hu7Department of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-sen UniversityDepartment of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-sen UniversityDepartment of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological diseases, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-sen UniversityDepartment of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-sen UniversityDepartment of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological diseases, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-sen UniversityDepartment of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-sen UniversityAbstract Background Neuroinflammation is a major driver of age-related brain degeneration and concomitant functional impairment. In patients with Alzheimer’s disease, the most common form of age-related dementia, factors that enhance neuroinflammation may exacerbate disease progression, in part by impairing the glymphatic system responsible for clearance of pathogenic beta-amyloid. Inflammatory bowel diseases (IBDs) induce neuroinflammation and exacerbate cognitive impairment in the elderly. The NACHT-LRR and pyrin (PYD) domain-containing protein 3 (NLRP3) inflammasome has been implicated in neuroinflammation. Therefore, we examined if the NLRP3 inflammasome contributes to glymphatic dysfunction and cognitive impairment in an aging mouse model of IBD. Methods Sixteen-month-old C57BL/6J and NLRP3 knockout (KO) mice received 1% wt/vol dextran sodium sulfate (DSS) in drinking water to model IBD. Colitis induction was confirmed by histopathology. Exploratory behavior was examined in the open field, associative memory by the novel-object recognition and Morris water maze tests, glymphatic clearance by in vivo two-photon imaging, and neuroinflammation by immunofluorescence and western blotting detection of inflammatory markers. Results Administration of DSS induced colitis, impaired spatial and recognition memory, activated microglia, and increased A1-like astrocyte numbers. In addition, DSS treatment impaired glymphatic clearance, aggravated amyloid plaque accumulation, and induced neuronal loss in the cortex and hippocampus. These neurodegenerative responses were associated with increased NLRP3 inflammasome expression and accumulation of gut-derived T lymphocytes along meningeal lymphatic vessels. Conversely, NLRP3 depletion protected against cognitive dysfunction, neuroinflammation, and neurological damage induced by DSS. Conclusions Colitis can exacerbate age-related neuropathology, while suppression of NLRP3 inflammasome activity may protect against these deleterious effects of colitis.https://doi.org/10.1186/s12974-021-02199-8Inflammatory bowel diseaseCognitionGlymphatic clearanceNLRP3 inflammasomeT cell |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xiao-fei He Li-li Li Wen-biao Xian Ming-yue Li Li-ying Zhang Jing-hui Xu Zhong Pei Hai-qing Zheng Xi-quan Hu |
spellingShingle |
Xiao-fei He Li-li Li Wen-biao Xian Ming-yue Li Li-ying Zhang Jing-hui Xu Zhong Pei Hai-qing Zheng Xi-quan Hu Chronic colitis exacerbates NLRP3-dependent neuroinflammation and cognitive impairment in middle-aged brain Journal of Neuroinflammation Inflammatory bowel disease Cognition Glymphatic clearance NLRP3 inflammasome T cell |
author_facet |
Xiao-fei He Li-li Li Wen-biao Xian Ming-yue Li Li-ying Zhang Jing-hui Xu Zhong Pei Hai-qing Zheng Xi-quan Hu |
author_sort |
Xiao-fei He |
title |
Chronic colitis exacerbates NLRP3-dependent neuroinflammation and cognitive impairment in middle-aged brain |
title_short |
Chronic colitis exacerbates NLRP3-dependent neuroinflammation and cognitive impairment in middle-aged brain |
title_full |
Chronic colitis exacerbates NLRP3-dependent neuroinflammation and cognitive impairment in middle-aged brain |
title_fullStr |
Chronic colitis exacerbates NLRP3-dependent neuroinflammation and cognitive impairment in middle-aged brain |
title_full_unstemmed |
Chronic colitis exacerbates NLRP3-dependent neuroinflammation and cognitive impairment in middle-aged brain |
title_sort |
chronic colitis exacerbates nlrp3-dependent neuroinflammation and cognitive impairment in middle-aged brain |
publisher |
BMC |
series |
Journal of Neuroinflammation |
issn |
1742-2094 |
publishDate |
2021-07-01 |
description |
Abstract Background Neuroinflammation is a major driver of age-related brain degeneration and concomitant functional impairment. In patients with Alzheimer’s disease, the most common form of age-related dementia, factors that enhance neuroinflammation may exacerbate disease progression, in part by impairing the glymphatic system responsible for clearance of pathogenic beta-amyloid. Inflammatory bowel diseases (IBDs) induce neuroinflammation and exacerbate cognitive impairment in the elderly. The NACHT-LRR and pyrin (PYD) domain-containing protein 3 (NLRP3) inflammasome has been implicated in neuroinflammation. Therefore, we examined if the NLRP3 inflammasome contributes to glymphatic dysfunction and cognitive impairment in an aging mouse model of IBD. Methods Sixteen-month-old C57BL/6J and NLRP3 knockout (KO) mice received 1% wt/vol dextran sodium sulfate (DSS) in drinking water to model IBD. Colitis induction was confirmed by histopathology. Exploratory behavior was examined in the open field, associative memory by the novel-object recognition and Morris water maze tests, glymphatic clearance by in vivo two-photon imaging, and neuroinflammation by immunofluorescence and western blotting detection of inflammatory markers. Results Administration of DSS induced colitis, impaired spatial and recognition memory, activated microglia, and increased A1-like astrocyte numbers. In addition, DSS treatment impaired glymphatic clearance, aggravated amyloid plaque accumulation, and induced neuronal loss in the cortex and hippocampus. These neurodegenerative responses were associated with increased NLRP3 inflammasome expression and accumulation of gut-derived T lymphocytes along meningeal lymphatic vessels. Conversely, NLRP3 depletion protected against cognitive dysfunction, neuroinflammation, and neurological damage induced by DSS. Conclusions Colitis can exacerbate age-related neuropathology, while suppression of NLRP3 inflammasome activity may protect against these deleterious effects of colitis. |
topic |
Inflammatory bowel disease Cognition Glymphatic clearance NLRP3 inflammasome T cell |
url |
https://doi.org/10.1186/s12974-021-02199-8 |
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