Abstract
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.
Highlights
Neuroinflammation is strongly implicated in the pathogenesis of age-related cognitive decline, including that associated with Alzheimer’s disease (AD), the most common form of dementia in older adults [1]
We found that oral administration of dextran sodium sulfate (DSS) to wild-type mice for 4 weeks increased NLRP3 inflammasome activity and gut-derived T cell numbers along meningeal lymphatic vessels, induced microglial and astrocyte activation, impaired glymphatic clearance of Aβ, and aggravated cognitive decline
We confirmed that DSS administration induced colitis in WT mice by hematoxylin and eosin (H&E) staining (Fig. 1B)
Summary
Neuroinflammation is strongly implicated in the pathogenesis of age-related cognitive decline, including that associated with Alzheimer’s disease (AD), the most common form of dementia in older adults [1]. The “glymphatic” pathway allows the exchange of para-arterial cerebrospinal fluid (CSF) with interstitial fluid (ISF) in the brain parenchyma, thereby promoting clearance of various toxic waste products from the central nervous system (CNS), including amyloid beta [5]. This pathway is markedly disrupted by neuroinflammation in aged brain [6, 7], which may lead to amyloid beta accumulation and concomitant neural damage. 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. We examined if the NLRP3 inflammasome contributes to glymphatic dysfunction and cognitive impairment in an aging mouse model of IBD
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