Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP/PS1 mice
Abstract
Activation of the inflammasome is implicated in the pathogenesis of an increasing number of inflammatory diseases, including Alzheimer's disease (AD). Research reporting inflammatory changes in post mortem brain tissue of individuals with AD and GWAS data have convincingly demonstrated that neuroinflammation is likely to be a key driver of the disease. This, together with the evidence that genetic variants in the NLRP3 gene impact on the risk of developing late-onset AD, indicates that targetting inflammation offers a therapeutic opportunity. Here, we examined the effect of the small molecule inhibitor of the NLRP3 inflammasome, MCC950, on microglia in vitro and in vivo. The findings indicate that MCC950 inhibited LPS+Aβ-induced caspase 1 activation in microglia and this was accompanied by IL-1β release, without inducing pyroptosis. We demonstrate that MCC950 also inhibited inflammasome activation and microglial activation in the APP/PS1 mouse model of AD. Furthermore, MCC950 stimulated Aβ phagocytosis in vitro, and it reduced Aβ accumulation in APP/PS1 mice, which was associated with improved cognitive function. These data suggest that activation of the inflammasome contributes to amyloid accumulation and to the deterioration of neuronal function in APP/PS1 mice and demonstrate that blocking assembly of the inflammasome may prove to be a valuable strategy for attenuating changes that negatively impact on neuronal function.
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Dempsey et al. found that deletion of NLRP3 or caspase-1 promoted microglia to anti-inflammatory phenotype, with reduced expression of IL-1β and caspase-1.
“Using the same model, Dempsey et al. found that deletion of NLRP3 or caspase-1 promoted microglia to anti-inflammatory phenotype, with reduced expression of IL-1β and caspase-1.355”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [355]
MCC950, a specific NLRP3 inhibitor, showed therapeutic effect in many neurodegenerative animal models.
“Indeed, MCC950, a specific NLRP3 inhibitor, showed therapeutic effect in many neurodegenerative animal models.355,356”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [355]
MCC950 reduces microglial activation, IL-1β secretion and Aβ plaque numbers, increases microglial phagocytosis of Aβ and improves cognitive function in APP/PS1 mice.
“For example, the NLRP3-specific small molecule inhibitor MCC950 was found to reduce microglial activation, IL-1β secretion and Aβ plaque numbers, increase microglial phagocytosis of Aβ and improve cognitive function in APP/PS1 mice [85, 86].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [86]
Pharmacological inhibition of NLRP3 inflammasome reduced Aβ deposition, neuroinflammation, and cognitive impairment in the APP/PS1 AD mouse model.
“In addition, the pharmacological inhibition of the NLRP3 inflammasome reduced Aβ deposition, neuroinflammation, and cognitive impairment in the APP/PS1 AD mouse model (231).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [231]
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- Authors
- Dempsey, C., Rubio Araiz, A., Bryson, K. J., Finucane, O., Larkin, C., Mills, E. L., Robertson, A. A. B., Cooper, M. A., O'Neill, L. A. J., & Lynch, M. A.
- Affiliations
- Trinity College Dublin (IE)
- The University of Queensland (AU)
- Corresponding author
- Lynch, M.A.
- Venue
- Brain Behavior and Immunity
- Publisher
- Elsevier BV
- Published
- 2017-03
- Volume
- 61
- Pages
- 306-316
- ISSN
- 0889-1591 (ISSN-L)
- OpenAlex
- W2566478676
- Cited by
- 571
- References
- 25
- Citations by year
- 2026: 61 · 2025: 76 · 2024: 62 · 2023: 75 · 2022: 72 · 2021: 74 · 2020: 75 · 2019: 38 · 2018: 29 · 2017: 9
- FWCI
- 13.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- NLRP3 inflammasome, MCC950, Alzheimer's disease, amyloid-beta clearance, microglia, neuroinflammation, caspase-1 activation, IL-1β, APP/PS1 mice, cognitive function, amyloid-beta phagocytosis, pyroptosis
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Alzheimer Disease, Animals, Cognition, Disease Models, Animal, Furans, Heterocyclic Compounds, 4 or More Rings, Indenes, Sulfonamides, Sulfones, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Microglia, Mice, Presenilin-1, Inflammasomes
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