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

Journal of Neuroinflammation

Zhong Pei¹  Wen-biao Xian¹  Hai-qing Zheng²  Xiao-fei He²  Li-li Li²  Jing-hui Xu²  Li-ying Zhang²  Xi-quan Hu²  Ming-yue Li² 

[1] Department 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 University, 510080, Guangzhou, Guangdong, China;Department of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-sen University, 600 Tianhe Road, 510630, Guangzhou, Guangdong, China;

关键词: Inflammatory bowel disease;    Cognition;    Glymphatic clearance;    NLRP3 inflammasome;    T cell;   

DOI  :  10.1186/s12974-021-02199-8

来源: Springer

【 摘 要 】

BackgroundNeuroinflammation 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.MethodsSixteen-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.ResultsAdministration 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.ConclusionsColitis can exacerbate age-related neuropathology, while suppression of NLRP3 inflammasome activity may protect against these deleterious effects of colitis.

【 授权许可】

CC BY