Chronic colitis exacerbates NLRP3-dependent neuroinflammation and cognitive impairment in middle-aged brain.
Chronic colitis exacerbates NLRP3-dependent neuroinflammation and cognitive impairment in middle-aged brain.
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慢性结肠炎加剧中年大脑中NLRP3依赖性神经炎症和认知障碍
DOI：
10.1186/s12974-021-02199-8
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发表时间：
2021-07-06
影响因子：
9.3
通讯作者：
Hu XQ
中科院分区：
文献类型：
--
作者：
He XF;Li LL;Xian WB;Li MY;Zhang LY;Xu JH;Pei Z;Zheng HQ;Hu XQ
神经炎症是与年龄相关的脑退化和伴随的功能障碍的主要驱动因素。在阿尔茨海默病患者中，增强神经炎症的因素可能会加剧疾病的进展，部分原因是通过损害负责清除致病的β-淀粉样蛋白的淋巴系统。阿尔茨海默病是最常见的年龄相关性痴呆症。炎症性肠病(IBD)可引起神经炎症，加重老年人的认知功能障碍。Nacht-LRR和PYD(PYD)结构域包含蛋白3(NLRP3)的炎症体与神经炎症有关。因此，我们研究了NLRP3炎症体是否与IBD老龄小鼠模型的淋巴功能障碍和认知功能障碍有关。16个月龄C57BL/6J和NLRP3基因敲除(KO)小鼠在饮水中加入1%质量分数的葡聚糖硫酸钠(DSS)建立IBD模型。结肠炎诱导经组织病理学证实。在旷场中检测探索行为，通过新对象识别和Morris水迷宫测试联想记忆，通过体内双光子成像检测淋巴清除，通过免疫荧光和免疫印迹检测炎症标志物来检测神经炎症。DSS诱导大鼠结肠炎，损害空间记忆和再认记忆，激活小胶质细胞，增加A1样星形胶质细胞数量。此外，DSS治疗损害了淋巴清除，加剧了淀粉样斑块的堆积，并诱导了皮质和海马神经元的丢失。这些神经退行性反应与NLRP3炎症体表达增加和肠源性T淋巴细胞沿脑膜淋巴管聚集有关。相反，NLRP3的缺失对DSS引起的认知功能障碍、神经炎症和神经损伤具有保护作用。结肠炎会加重与年龄相关的神经病理，而抑制NLRP3炎症体活性可能会预防结肠炎的这些有害影响。网上版载有补充材料，可在10.1186/s12974-021-02199-8查阅。
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. 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. 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. Colitis can exacerbate age-related neuropathology, while suppression of NLRP3 inflammasome activity may protect against these deleterious effects of colitis. The online version contains supplementary material available at 10.1186/s12974-021-02199-8.
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影响因子：
11.2
作者：
Kaufman, Adam C.;Salazar, Santiago V.;Haas, Laura T.;Yang, Jinhee;Kostylev, Mikhail A.;Jeng, Amanda T.;Robinson, Sophie A.;Gunther, Erik C.;van Dyck, Christopher H.;Nygaard, Haakon B.;Strittmatter, Stephen M.
通讯作者：
Strittmatter, Stephen M.
影响因子：
82.9
作者：
Benakis C;Brea D;Caballero S;Faraco G;Moore J;Murphy M;Sita G;Racchumi G;Ling L;Pamer EG;Iadecola C;Anrather J
通讯作者：
Anrather J
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
5.6
作者：
Chen, Jiali;Jayachandran, Muthukumaran;Xu, Baojun
通讯作者：
Xu, Baojun
影响因子：
64.8
作者：
Ahn, Ji Hoon;Cho, Hyunsoo;Koh, Gou Young
通讯作者：
Koh, Gou Young