Chronic colitis exacerbates NLRP3-dependent neuroinflammation and cognitive impairment in middle-aged brain

作者：Xiaofei He, Lili Li, Wenbiao Xian, Mingyue Li, Liying Zhang, Jinghui Xu, Zhong Pei, Haiqing Zheng, Xiquan Hu · 发表于：Journal of Neuroinflammation · 年份：2021 · DOI：10.1186/s12974-021-02199-8 · 被引用次数：111 · 研究领域：Cerebrospinal fluid and hydrocephalus、Gut microbiota and health、Tryptophan and brain disorders

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 neur...